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WO2018035410A1 - Compositions et procédés de traitement utilisant des analogues d'adn de taille étendue - Google Patents

Compositions et procédés de traitement utilisant des analogues d'adn de taille étendue Download PDF

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WO2018035410A1
WO2018035410A1 PCT/US2017/047508 US2017047508W WO2018035410A1 WO 2018035410 A1 WO2018035410 A1 WO 2018035410A1 US 2017047508 W US2017047508 W US 2017047508W WO 2018035410 A1 WO2018035410 A1 WO 2018035410A1
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substituted
alkyl
phenyl
heteroaryl
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Richard T. POMERANTZ
Eric T. Kool
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Temple Univ School of Medicine
Leland Stanford Junior University
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Temple Univ School of Medicine
Leland Stanford Junior University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/24—Heterocyclic radicals containing oxygen or sulfur as ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/23—Heterocyclic radicals containing two or more heterocyclic rings condensed among themselves or condensed with a common carbocyclic ring system, not provided for in groups C07H19/14 - C07H19/22

Definitions

  • Synthetic nucleotide analogs possessing non-canonical structures and properties are widely used for medicinal purposes, biomedical research, high-throughput sequencing, and show promise for synthetic biology applications (Jordheim et al., 2013, Nat Rev Drug Discov 12:447-64; Guo et al., 2008, PNAS 105:9145-50; Chen, 2014, Frong Microbiol 5:305; Krueger et al., 2011, J Am Chem Soc 133 : 18447-51; Liu et al., 2003, Science 302:868-71; Malyshev et al., 2014, Nature 509:385-8).
  • nucleoside and nucleotide analogs have been developed widely as prodrugs to treat cancer and viral infections (Jordheim et al., 2013, Nat Rev Drug Discov 12:447-64).
  • HCV anti-hepatitis C virus
  • the anti-hepatitis C virus (HCV) nucleotide prodrug sofosbuvir is now widely used to treat HCV patients due to its ability to act as a chain terminator of HCV NS5A polymerase after it is converted into triphosphate form in cells (Jordheim et al., 2013, Nat Rev Drug Discov 12:447-64; Gane et al., 2013, NEJM 368:34-44).
  • nucleoside and nucleotide analogs are also used as chemotherapy agents for both hematological malignancies and solid tumors.
  • gemcitabine a prodrug deoxycytidine analog that inhibits DNA synthesis, is used to treat various carcinomas including pancreatic cancer, non-small cell lung cancer, breast cancer, bladder cancer, and is currently being tested in blood cancers (Jordheim et al., 2013, Nat Rev Drug Discov 12:447-64).
  • Sapacitabine is a newly developed nucleoside analog that exhibits a unique mechanism of action by catalyzing a single-strand break in DNA after its incorporated by the replication machinery (Jordheim et al., 2013, Nat Rev Drug Discov 12:447-64).
  • the single-strand break is subsequently converted into a double- strand break (DSB) during the next round of replication.
  • DSB double- strand break
  • HR homologous recombination
  • sapacitabine causes selective killing of cells deficient in HR, which is a proven mechanism of personalized medicine for cancers mutated in integral HR factors such as BRCA1 or BRCA2 (Liu et al., 2012, Chin J Cancer 31 :373-80; Lord et al., 2014, Annu Rev Med 66:455-70).
  • Synthetic nucleotide analogs also show great promise for synthetic biology applications.
  • unnatural nucleotides containing hydrophobic nucleobases or alternatively-H-bonded nucleobases have recently been developed for the purpose of expanding the genetic code (Malyshev et al., 2014, Nature 509:385-8; Zhang et al., 2014, J Am Chem Soc 137:6734-7; Yamashige et al., 2012, NAR, 40:2793-806).
  • Such alternative base pairs can adopt a Watson-Crick-compatible pair geometry within a polymerase active site, and at least one example can be incorporated during multiple rounds of DNA replication in bacteria (Malyshev et al., 2014, Nature 509:385-8; Betz et al., 2012, Nat Chem Biol 8:612-4).
  • dxNMPs deoxyribonucleoside monophosphates
  • dxNTPs triphosphates
  • Y-family DNA polymerase Dpo4 was shown to perform relatively efficient nucleotide incorporation opposite template dxNMPs in vitro, in comparison to A family Pol I (Klenow fragment) which exhibits higher fidelity DNA synthesis (Lu et al., 2010, Org Biomol Chem 8:2704-10). Together, these studies demonstrate that certain sterically flexible DNA polymerases can accommodate size- expanded dxNMPs in the template DNA strand.
  • deoxynucleotidyl transferase which unlike common DNA polymerases does not require a template for the nucleotidyl transfer, thus potentially explaining its ability to
  • translesion polymerases are also capable of incorporating nucleotides containing structurally altered or enlarged bases that arise from oxidative damage (Shimizu et al., 2003, EMBO Rep 4:269-73 Atafuchi et al., 2010, NAR 38:859-67; Foti et al., 2012, Science 336:315-9).
  • certain translesion polymerases may effectively utilize size-expanded nucleotides as substrates for DNA synthesis.
  • DNA polymerase ⁇ ( ⁇ )— has been characterized as a highly promiscuous enzyme that exhibits translesion synthesis activity and the unique ability to synthesize DNA across a DSB during a process called microhomology- mediated end-joining (MMEJ) or alternative end-joining (alt-EJ) (Kent et al., 2015, Nat Struct Mol biol 22:230-7; Hogg et al., 2011, J Mol Biol 405:642-52; Seki and Wood, 2008, DNA Repair 7: 119-27; Arana et al., 2008, NAR 36:3847-56; Hogg et al., 2012, NAR 40:2611-22).
  • MMEJ microhomology- mediated end-joining
  • alt-EJ alternative end-joining
  • ⁇ is among the A-family of polymerases, it exhibits low-fidelity DNA synthesis and translesion synthesis activities akin to Y-family polymerases.
  • the translesion synthesis activity of ⁇ has been attributed to a unique insertion motif which has also been shown to facilitate MMEJ (Kent et al., 2015, Nat Struct Mol biol 22:230-7; Hogg et al., 2011, J Mol Biol 405:642-52).
  • ⁇ extends minimally paired ssDNA overhangs generated by 5 '-3' exonucleases at DSBs which is necessary for end-joining of the broken DNA ends (Kent et al., 2015, Nat Struct Mol biol 22:230-7).
  • ⁇ is highly upregulated in multiple cancer types, and high levels of the polymerase have been shown to correspond to a poor survival rate for breast cancer patients regardless of their specific breast cancer type (Lemee et al., 2010, PNAS
  • ⁇ has also been shown to confer resistance to ionizing radiation and other chemotherapy agents such as the Poly (ADP ribose) polymerase I (PARPl) inhibitor Olaparib, which has recently been approved to treat ovarian cancer patients harboring mutations in integral HR factors BRCA1 or BRCA2 (BRCA) (Higgins et al., 2010, Cancer Res 70:2984-93; Ceccaldi et al., 2015, Nature 517:258-62 -34;
  • ⁇ confers radiation resistance onto cancer cells in general, and promotes resistance to other chemotherapy agents that cause genotoxic stress (Higgins et al., 2010, Cancer Res 70:2984-93; Ceccaldi et al., 2015, Nature 517:258-62 -34; Yousefzadeh et al.,2014, PLoS Genet 10:el004654), it is important to identify selective drug inhibitors of ⁇ for the treatment of a variety of cancer types.
  • compositions and methods for inhibiting DNA polymerase theta ( ⁇ ) and treating cancer There is thus a need in the art for compositions and methods for inhibiting DNA polymerase theta ( ⁇ ) and treating cancer.
  • the present invention addresses this unmet need in the art.
  • the invention provides a compound represented by one of Formulae (I) to (IV):
  • A is an optionally substituted 4 to 6 membered aromatic or heteroaromatic ring; each occurrence of X 1 is independently selected from the group consisting of CR 19 , and N;
  • R 11 to R 15 are each independently selected from the group consisting of H, Fl, CI, Br, I, - R 19 R 110 , -OH, Ci-Ce alkyl, substituted Ci-Ce alkyl, Ci-Ce alkenyl, substituted Ci-C 6 alkenyl, Ci-C 6 alkynyl, substituted Ci-C 6 alkynyl, aiyl, substituted aiyl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -(Ci-Ce)alkyl-phenyl, -(Ci-C6)alkyl-substituted phenyl,
  • R 16 is selected from the group consisting of OH, -N 3 , F, CI, and H;
  • each occurrence of R 17 and R 18 is independently selected from the group consisting of H, - R 19 R 110 , -OR 19 , -O " , Ci-Ce alkyl, substituted Ci-Ce alkyl, aiyl, substituted aiyl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -(Ci-Ce)alkyl-phenyl, substituted -(Ci- C 6 )alkyl- phenyl, -(Ci-C6)alkyl-carbocyclyl, -(Ci-C6)alkyl-heteroaryl, and substituted -(Ci-Ce)alkyl- heteroaryl;
  • X is selected from the group consisting of O, and R 19 ;
  • each occurrence of R 19 is independently is selected from the group consisting of H, Ci-Ce alkyl, substituted Ci-Ce alkyl, aiyl, substituted aiyl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, N(R 110 )(R 1 U ), -(Ci-C 6 )alkyl-phenyl, substituted -(Ci-C 6 )alkyl- phenyl, -(Ci-C6)alkyl-carbocyclyl, -(Ci-C6)alkyl-heteroaryl, and substituted -(Ci-Ce)alkyl- heteroaryl;
  • each occurrence of R 110 and R 111 is independently is selected from the group consisting of H, Ci-C 6 alkyl, substituted Ci-C 6 alkyl, aiyl, substituted aiyl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -(Ci-Ce)alkyl-phenyl, substituted -(Ci-Ce)alkyl- phenyl, -(Ci-C6)alkyl-carbocyclyl, -(Ci-C6)alkyl-heteroaryl, and substituted -(Ci-Ce)alkyl- heteroaryl; and
  • R 21 to R 25 are each independently selected from the group consisting of H, Fl, CI, Br, I, - R 29 R 210 , -OH, Ci-Ce alkyl, substituted Ci-C 6 alkyl, Ci-C 6 alkenyl, substituted Ci-C 6 alkenyl, Ci-C 6 alkynyl, substituted Ci-C 6 alkynyl, aryl, substituted aryl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -(Ci-Ce)alkyl- phenyl, -(Ci-C6)alkyl-substituted phenyl, -(Ci-C6)alkyl-carbocyclyl,
  • R 26 is selected from the group consisting of OH, -N 3 , F, CI, and H;
  • each occurrence of R 27 and R 28 is independently selected from the group consisting of H, - R 29 R 210 , -OR 29 , -O " , Ci-Ce alkyl, substituted Ci-Ce alkyl, aryl, substituted aryl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -(Ci-Ce)alkyl-phenyl, substituted -(Ci- C 6 )alkyl- phenyl, -(Ci-C6)alkyl-carbocyclyl, -(Ci-C6)alkyl-heteroaryl, and substituted -(Ci-Ce)alkyl- heteroaryl;
  • X 1 is selected from the group consisting of O, and R 29 ;
  • X 2 is selected from the group consisting of O, and S;
  • each occurrence of R 29 and R 210 is independently is selected from the group consisting of H, Ci-Ce alkyl, substituted Ci-Ce alkyl, aryl, substituted aryl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -(Ci-Ce)alkyl-phenyl, substituted -(Ci-Ce)alkyl- phenyl, -(Ci-C6)alkyl-carbocyclyl, -(Ci-C6)alkyl-heteroaryl, and substituted -(Ci-Ce)alkyl- heteroaryl; and
  • n is an integer from 0-3.
  • R 31 to R 35 are each independently selected from the group consisting of H, Fl, CI, Br, I, - R 39 R 310 , -OH, Ci-Ce alkyl, substituted Ci-C 6 alkyl, Ci-C 6 alkenyl, substituted Ci-C 6 alkenyl, Ci-C 6 alkynyl, substituted Ci-C 6 alkynyl, aryl, substituted aryl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -(Ci-C 6 )alkyl- phenyl, -(Ci-C6)alkyl-substituted phenyl, -(Ci-C6)alkyl-carbocyclyl,
  • R 36 is selected from the group consisting of OH, -N 3 , F, CI, and H; each occurrence of R and R is independently selected from the group consisting of H, - R 39 R 310 , -OR 39 , -O " , Ci-Ce alkyl, substituted Ci-Ce alkyl, aiyl, substituted aiyl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -(Ci-Ce)alkyl-phenyl, substituted -(Ci- C 6 )alkyl- phenyl, -(Ci-C6)alkyl-carbocyclyl, -(Ci-C6)alkyl-heteroaryl, and substituted -(Ci-Ce)alkyl- heteroaryl;
  • X 1 is selected from the group consisting of O, and R 39 ;
  • X 3 is selected from the group consisting of O and S;
  • each occurrence of R 39 and R 310 is independently is selected from the group consisting of H, Ci-Ce alkyl, substituted C1-G5 alkyl, aiyl, substituted aiyl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -(Ci-Ce)alkyl-phenyl, substituted -(Ci-Ce)alkyl- phenyl, -(Ci-C6)alkyl-carbocyclyl, -(Ci-C6)alkyl-heteroaryl, and substituted -(Ci-Ce)alkyl- heteroaryl; and
  • n is an integer from 0-3.
  • B is an optionally substituted 4 to 6 membered aromatic or heteroaromatic ring
  • X is selected from the group consisting of O, and NR 49 ;
  • X I is selected from the group consisting of N and CR 49 ,
  • X 2 is selected from the group consisting of O, S, NR 49 , and C(R 49 )(R 410 )
  • X 3 is selected from the group consisting of O and S;
  • R 41 to R 45 are each independently selected from the group consisting of H, Fl, CI, Br, I, - R 49 R 410 , -OH, Ci-Ce alkyl, substituted Ci-Ce alkyl, Ci-Ce alkenyl, substituted Ci-C 6 alkenyl, Ci-C 6 alkynyl, substituted Ci-C 6 alkynyl, aiyl, substituted aiyl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -(Ci-Ce)alkyl-phenyl, -(Ci-C6)alkyl-substituted phenyl,
  • R 46 is selected from the group consisting of OH, -N 3 , F, CI, and H;
  • each occurrence of R 47 and R 48 is independently selected from the group consisting of H, - R 49 R 410 , -OR 49 , -O " , Ci-Ce alkyl, substituted Ci-Ce alkyl, aiyl, substituted aryl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -(Ci-C6)alkyl-phenyl, substituted -(Ci- C 6 )alkyl- phenyl, -(Ci-C6)alkyl-carbocyclyl, -(Ci-C6)alkyl-heteroaryl, and substituted -(Ci-Ce)alkyl- heteroaryl;
  • each occurrence of R 49 and R 410 is independently is selected from the group consisting of H, Ci-Ce alkyl, substituted Ci-C 6 alkyl, aryl, substituted aryl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -(Ci-Ce)alkyl-phenyl, substituted -(Ci-Ce)alkyl- phenyl, substituted -(Ci-Ce)alkyl- phenyl,
  • n is an integer from 0-3.
  • R 18 , R 28 , R 38 , and R 48 are each independently selected from the group consisting of H, and phenyl.
  • R 17 , R 27 , R 37 , and R 47 are each independently selected from the group consisting of substituted Ci-C 6 alkyl, and propan-2-yl 2-aminopropanoate.
  • R represents a phosphate prodrug
  • the compound of Formula (I) is a compound of
  • R 11 to R 15 are each independently selected from the group consisting of H, Fl, CI, Br, I, - R 19 R 110 , -OH, Ci-Ce alkyl, substituted Ci-Ce alkyl, Ci-Ce alkenyl, substituted Ci-C 6 alkenyl, Ci-C 6 alkynyl, substituted Ci-C 6 alkynyl, aiyl, substituted aiyl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -(Ci-Ce)alkyl-phenyl, -(Ci-C6)alkyl-substituted phenyl,
  • R 16 is selected from the group consisting of OH, -N 3 , F, CI, and H;
  • each occurrence of R 17 and R 18 is independently selected from the group consisting of H, - R 19 R 110 , -OR 19 , -O " , Ci-Ce alkyl, substituted Ci-Ce alkyl, aiyl, substituted aiyl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -(Ci-Ce)alkyl-phenyl, substituted -(Ci- C 6 )alkyl- phenyl, -(Ci-C6)alkyl-carbocyclyl, -(Ci-C6)alkyl-heteroaryl, and substituted -(Ci-C 6 )alkyl- heteroaryl;
  • X is selected from the group consisting of O, and NR ;
  • each occurrence of R 19 and R 110 is independently is selected from the group consisting of H, Ci-Ce alkyl, substituted C1-G5 alkyl, aiyl, substituted aiyl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -(Ci-Ce)alkyl-phenyl, substituted -(Ci-Ce)alkyl- phenyl, -(Ci-C6)alkyl-carbocyclyl, -(Ci-C6)alkyl-heteroaryl, and substituted -(Ci-Ce)alkyl- heteroaryl; and
  • n is an integer from 0-3.
  • the compound of Formula (IV) is a compound of
  • R 41 to R 45 are each independently selected from the group consisting of H, Fl, CI, Br, I, - R 49 R 410 , -OH, Ci-Ce alkyl, substituted Ci-Ce alkyl, Ci-Ce alkenyl, substituted Ci- C 6 alkenyl, Ci-C 6 alkynyl, substituted Ci-C 6 alkynyl, aiyl, substituted aiyl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -(Ci-Ce)alkyl-phenyl, -(Ci-C6)alkyl-substituted phenyl, -(Ci-C 6 )alkyl- carbocyclyl, -(Ci-C6)alkyl-heteroaryl, and -(Ci-C6)alkyl-substituted heteroaryl;
  • R 46 is selected from the group consisting of OH, -N 3 , F, CI, and H;
  • each occurrence of R 47 and R 48 is independently selected from the group consisting of H, - R 49 R 410 , -OR 49 , -O " , Ci-Ce alkyl, substituted Ci-Ce alkyl, aiyl, substituted aiyl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -(Ci-Ce)alkyl-phenyl, substituted -(Ci- C 6 )alkyl- phenyl, -(Ci-C6)alkyl-carbocyclyl, -(Ci-C6)alkyl-heteroaryl, and substituted -(Ci-Ce)alkyl- heteroaryl;
  • X is selected from the group consisting of O, and NR 49 ; each occurrence of R 49 and R 410 is independently is selected from the group consisting of H, C1-G5 alkyl, substituted C1-G5 alkyl, aryl, substituted aryl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -(Ci-Ce)alkyl-phenyl, substituted -(Ci-Ce)alkyl- phenyl, -(Ci-Ce)alkyl- carbocyclyl, -(Ci-C6)alkyl-heteroaryl, and substituted -(Ci-Ce)alkyl- heteroaryl; and n is an integer from 0-3.
  • the invention provides a composition comprising a compound of one of Formula (I) to (IV).
  • the composition further comprises a pharmaceutically acceptable carrier.
  • the invention provides a method of inhibiting ⁇ in a subject in need thereof.
  • the method comprises administering to the subject a therapeutically effective amount of a composition comprising at least one compound represented by one of Formulae (I) to (IV).
  • the invention provides a method of treating cancer in a subject.
  • the method comprises administering effective amount of a composition comprising a compound represented by one of Formulae (I) to (IV).
  • the method further comprises administering to the subject at least one additional therapeutic agent.
  • the therapeutic agent is selected from the group consisting of a chemotherapy, chemotherapeutic agent, radiation therapy, hormonal therapy, and any combination thereof.
  • the therapeutic agent is selected from the group consisting of Olaparib and cisplatin.
  • the cancer is resistant to at least one chemotherapy. In one embodiment, the cancer is breast cancer. BRIEF DESCRIPTION OF THE DRAWINGS
  • Figure 1 depicts results from experiments demonstrating that purified ⁇ effectively incorporates dxNMPs.
  • Figure 1 A depicts the structures of dxNTPs.
  • Figure IB depicts a denaturing gel showing ⁇ primer extension in the presence of dCTP and dxCTP.
  • Figure 1C depicts a denaturing gel showing ⁇ primer extension in the presence of dGTP and dxGTP.
  • Figure ID depicts a denaturing gel showing ⁇ primer extension in the presence of dATP and dxATP.
  • Figure IE depicts a denaturing gel showing ⁇ primer extension in the presence of dTTP and dxTTP.
  • Figure 2 depicts results from experiments demonstrating Y-family polymerases exhibit a limited ability to incorporate dxNMPs.
  • Figure 2A depicts a denaturing gel showing ⁇ primer extension in the presence of dCTP and dxCTP.
  • Figure 2B depicts a denaturing gel showing ⁇ primer extension in the presence of dGTP and dxGTP.
  • Figure 2C depicts a denaturing gel showing ⁇ primer extension in the presence of dATP and dxATP.
  • Figure 2D depicts a denaturing gel showing ⁇ primer extension in the presence of dTTP and dxTTP.
  • Figure 2E depicts a denaturing gel showing ⁇ primer extension in the presence of dCTP and dxCTP.
  • Figure 2F depicts a denaturing gel showing ⁇ primer extension in the presence of dGTP and dxGTP.
  • Figure 2G depicts a denaturing gel showing ⁇ primer extension in the presence of dATP and dxATP.
  • Figure 2H depicts a denaturing gel showing ⁇ primer extension in the presence of dTTP and dxTTP.
  • Figure 3 depicts results from experiments demonstrating X-family polymerase ⁇ fails to incorporate dxNMPs.
  • Figure 3 A depicts a denaturing gel showing primer extension by Pol ⁇ in the presence of dCTP and dxCTP.
  • Figure 3B depicts a denaturing gel showing primer extension by Pol ⁇ in the presence of dGTP and dxGTP.
  • Figure 3C depicts a denaturing gel showing primer extension by Pol ⁇ in the presence of dATP and dxATP.
  • Figure 3D depicts a denaturing gel showing primer extension by Pol ⁇ in the presence of dTTP and dxTTP.
  • Figure 3E depicts a denaturing gel showing primer extension on a template containing a small gap by Pol ⁇ in the presence of dCTP and dxCTP.
  • Figure 3F depicts a denaturing gel showing primer extension on a template containing a small gap by Pol ⁇ in the presence of dGTP and dxGTP.
  • Figure 4 comprising Figure 4A through Figure 4E, depicts results from experiments demonstrating B-family and A-family replicative polymerases fail to stably incorporate dxNMPs.
  • Figure 4A depicts a denaturing gel showing primer extension in the presence of ⁇ or ⁇ , dT, dA, dC, and dxG, with or without dGTP rescue.
  • Figure 4B depicts a denaturing gel showing primer extension in the presence of ⁇ or ⁇ , dT, dA, dG, and dxC, with or without dCTP rescue.
  • Figure 4C depicts a model of ⁇ and ⁇ activities. ⁇ and ⁇ exonuclease activities are stimulated by the presence of a complementary dxNTP (dxGTP). However, the subsequent addition of the respective canonical dNTP (dGTP) rescues their ability to perform replication.
  • Figure 4D depicts a denaturing gel showing primer extension by Pola in the presence of dCTP and dxCTP (left panel), and dGTP and dxGTP (right panel).
  • Figure 4E depicts a denaturing gel showing primer extension by ⁇ in the presence of dCTP and dxCTP (left panel), and dGTP and dxGTP (right panel).
  • Figure 5 depicts results from experiments demonstrating ⁇ is inhibited after multiple dx MP incorporation events.
  • Figure 5 A depicts a denaturing gel showing ⁇ primer-template extension in the presence of the indicated nucleotides and primer-template sequence.
  • Figure 5B depicts a denaturing gel showing ⁇ primer-template extension in the presence of a mixture of dNTPs or dxNTPs and the indicated primer-template sequence.
  • Figure 5C depicts a denaturing gel showing ⁇ primer-template extension in the presence of a mixture of dNTPs or dxNTPs and the indicated primer-template sequence.
  • Figure 5D depicts a denaturing gel showing ⁇ primer-template extension in the presence of a mixture of dNTPs and dxNTPs and the indicated primer-template sequence.
  • Figure 5E depicts a model of ⁇ activity. ⁇ becomes arrested after incorporating two consecutive dxGMPs probably due to steric hindrance within its active site.
  • Figure 5F depicts a denaturing gel showing ⁇ primer-template extension in the presence of the indicated concentrations of dNTPs and dxGTP. ⁇ becomes arrested in the presence of increasing concentrations of dxGTP.
  • Figure 6 depicts results from experiments demonstrating ⁇ exhibits a relatively high efficiency of dxGMP incorporation.
  • Figure 6A depicts denaturing gels showing a time course of ⁇ primer extension in the presence of the indicated expanded-size dxNTP.
  • Figure 6B depicts a plot showing relative velocities of ⁇ incorporation of dx MPs.
  • Figure 6C depicts plots showing relative velocity of ⁇ incorporation of the indicated nucleotide.
  • Figure 6D depicts Hanes-Woolf plots of ⁇ steady-state incorporation of the indicated nucleotide. Each data point represents an average from three separate experiments. Relative Km, Vmax and Vmax / Km are indicated.
  • Figure 6E depicts a denaturing gel showing ⁇ primer extension in the presence of the indicated nucleotides and a schematic illustrating the ability of dxGTP to compete with dGTP during ⁇ primer extension.
  • Figure 7 depicts results from experiments demonstrating X-family polymerases fail to efficiently incorporate dxNMPs. Shown are denaturing gels showing primer extension by the indicated polymerase in the presence of the indicated nucleotide and primer-template sequence.
  • Figure 8 depicts the chemical structures of xA nucleotide, nucleoside and prodrug nucleotide analogs.
  • Figure 9 depicts the chemical structures of xG nucleotide nucleoside and prodrug nucleotide analogs.
  • Figure 10 depicts the chemical structures of xC and xT nucleotide nucleoside and prodrug nucleotide analogs.
  • the present invention relates to the unexpected discovery that size- expanded DNA (xDNA) deoxyribonucleoside monophosphate analogs (dxNMPs) are selectively and efficiently incorporated by ⁇ , and inhibit the DNA synthesis activity of ⁇ .
  • xDNA size- expanded DNA
  • dxNMPs deoxyribonucleoside monophosphate analogs
  • the present invention is directed to methods and compositions for inhibiting ⁇ in vitro and in vivo.
  • ⁇ is essential for the survival of cancer cells, accordingly, the present invention also provides methods and compositions for treating cancer with dxNMP based nucleoside and nucleotide analogs.
  • an element means one element or more than one element.
  • “About” as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ⁇ 20% or in some instances ⁇ 10%, or in some instances ⁇ 5%, or in some instances ⁇ 1%, or in some instances ⁇ 0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.
  • a “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal's health continues to deteriorate.
  • a disorder in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal's state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal's state of health.
  • the term "anti-tumor effect” as used herein refers to a biological effect which can be manifested by a decrease in tumor volume, a decrease in the number of tumor cells, a decrease in the number of metastases, an increase in life expectancy, or amelioration of various physiological symptoms associated with the cancerous condition.
  • An "anti-tumor effect” can also be manifested by the ability of the peptides, polynucleotides, cells and antibodies of the invention in prevention of the occurrence of tumor in the first place.
  • cancer refers to any of various types of malignant neoplasms, most of which invade surrounding tissues, may metastasize to several sites and are likely to recur after attempted removal and to cause death of the patient unless adequately treated.
  • neoplasia comprises cancer.
  • Representative cancers include, for example, squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias, including non-acute and acute leukemias, such as acute myelogenous leukemia, acute lymphocytic leukemia, acute promyelocytic leukemia (APL), acute T-cell lymphoblastic leukemia, T-lineage acute lymphoblastic leukemia (T-ALL), adult T-cell leukemia, basophilic leukemia, eosinophilic leukemia, granulocytic leukemia, hairy cell leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, megakaryocyte le
  • Effective amount or “therapeutically effective amount” are used interchangeably herein, and refer to an amount of a compound, formulation, material, or composition, as described herein effective to achieve a particular biological result. Such results may include, but are not limited to, the inhibition of virus infection as determined by any means suitable in the art.
  • inhibitor means to suppress or block an activity or function by at least about ten percent relative to a control value.
  • the activity is suppressed or blocked by 50% compared to a control value, more preferably by 75%, and even more preferably by 95% or more.
  • A refers to adenosine
  • C refers to cytosine
  • G refers to guanosine
  • T refers to thymidine
  • U refers to uridine.
  • nucleotide sequence encoding an amino acid sequence includes all nucleotide sequences that are degenerate versions of each other and that encode the same amino acid sequence.
  • the phrase nucleotide sequence that encodes a protein or an RNA may also include introns to the extent that the nucleotide sequence encoding the protein may in some version contain an intron(s).
  • co-administered and “co-administration” as relating to a subject refer to administering to the subject a compound useful within the invention, or salt thereof, along with a compound that may also treat any of the diseases contemplated within the invention.
  • the co-administered compounds are administered separately, or in any kind of combination as part of a single therapeutic approach.
  • the co-administered compound may be formulated in any kind of
  • the term "pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing an undesirable biological effect or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • the language "pharmaceutically acceptable salt” refers to a salt of the administered compound prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids, organic acids, solvates, hydrates, or clathrates thereof.
  • inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, acetic, hexafluorophosphoric, citric, gluconic, benzoic, propionic, butyric, sulfosalicylic, maleic, lauric, malic, fumaric, succinic, tartaric, amsonic, pamoic, p-tolunenesulfonic, and mesylic.
  • organic acids may be selected, for example, from aliphatic, aromatic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, camphorsulfonic, citric, fumaric, gluconic, isethionic, lactic, malic, mucic, tartaric, para-toluenesulfonic, glycolic, glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, pantothenic, benzenesulfonic (besylate), stearic, sulfanilic, alginic, galacturonic, and the like.
  • pharmaceutically acceptable salts include, by way of non-limiting example, alkaline earth metal salts (e.g., calcium or magnesium), alkali metal salt
  • the term "pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the patient such that it may perform its intended function.
  • a pharmaceutically acceptable material, composition or carrier such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the patient such that it may perform its intended function.
  • Such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the invention, and not injurious to the patient.
  • materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline
  • pharmaceutically acceptable carrier also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the invention, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions.
  • the "pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within the invention.
  • Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the invention are known in the art and described, for example in
  • an "effective amount" of a delivery vehicle is that amount sufficient to effectively bind or deliver a compound.
  • alkyl by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated (i.e. Ci-6 means one to six carbon atoms) and including straight, branched chain, or cyclic substituent groups. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, and cyclopropylmethyl.
  • substituted alkyls include, but are not limited to, 2,2-difluoropropyl,
  • heteroalkyl by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized.
  • the heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group. Examples include: -O-CH2-CH2-CH3, -CH2-CH2-CH2-OH, -CH2-CH2- H-CH3,
  • -CH2-S-CH2-CH3, and -CH2CH2-S( 0)-CH3.
  • Up to two heteroatoms may be consecutive, such as, for example, -CH2- H-OCH3, or -CH2-CH2-S-S-CH3
  • alkoxy employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms, as defined above, connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers.
  • halo or halogen alone or as part of another substituent means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • cycloalkyl refers to a mono cyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom.
  • the cycloalkyl group is saturated or partially
  • cycloalkyl group is fused with an aromatic ring.
  • Cycloalkyl groups include groups having from 3 to 10 ring atoms.
  • Illustrative examples of cycloalkyl groups include, but are not limited to, the following
  • Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Dicyclic cycloalkyls include, but are not limited to, tetrahydronaphthyl, indanyl, and tetrahydropentalene.
  • Polycyclic cycloalkyls include adamantine and norbornane.
  • cycloalkyl includes "unsaturated nonaromatic carbocyclyl” or “nonaromatic unsaturated carbocyclyl” groups, both of which refer to a nonaromatic carbocycle as defined herein, which contains at least one carbon double bond or one carbon triple bond.
  • heterocycloalkyl refers to a heteroalicyclic group containing one to four ring heteroatoms each selected from O, S and N.
  • each heterocycloalkyl group has from 4 to 10 atoms in its ring system, with the proviso that the ring of said group does not contain two adjacent O or S atoms.
  • the heterocycloalkyl group is fused with an aromatic ring.
  • the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen atom may be optionally quaternized.
  • the heterocyclic system may be attached, unless otherwise stated, at any heteroatom or carbon atom that affords a stable structure.
  • a heterocycle may be aromatic or non-aromatic in nature.
  • the heterocycle is a heteroaryl.
  • 3-membered heterocycloalkyl group includes, and is not limited to, aziridine.
  • 4-membered heterocycloalkyl groups include, and are not limited to, azetidine and a beta lactam.
  • 5-membered heterocycloalkyl groups include, and are not limited to, pyrrolidine, oxazolidine and thiazolidinedione.
  • 6-membered heterocycloalkyl groups include, and are not limited to, piped dine, morpholine and piperazine.
  • non-aromatic heterocycles include monocyclic groups such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, pyrazolidine, imidazoline, dioxolane, sulfolane, 2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane, piperidine, 1,2,3, 6-tetrahydropyridine, 1,4-dihydropyridine, piperazine, morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dioxane, 1,3-dioxane, homopiperazine, horn opiperi dine, 1,3-dioxepane,
  • aromatic refers to a carbocycle or heterocycle with one or more polyunsaturated rings and having aromatic character, i.e. having (4n + 2) delocalized ⁇ (pi) electrons, where n is an integer.
  • aryl employed alone or in combination with other terms, means, unless otherwise stated, a carbocyclic aromatic system containing one or more rings (typically one, two or three rings), wherein such rings may be attached together in a pendent manner, such as a biphenyl, or may be fused, such as naphthalene.
  • aryl groups include phenyl, anthracyl, and naphthyl.
  • aryl-(Ci-C3)alkyl means a functional group wherein a one- to three-carbon alkylene chain is attached to an aryl group, e.g., -CH 2 CH2-phenyl. Preferred is aryl-CH 2 - and aryl-CH(CH 3 )-.
  • substituted aryl-(Ci-C 3 )alkyl means an aryl-(Ci-C 3 )alkyl functional group in which the aryl group is substituted.
  • heteroaryl-(Ci-C 3 )alkyl means a functional group wherein a one to three carbon alkylene chain is attached to a heteroaryl group, e.g., -CH 2 CH 2 -pyridyl.
  • substituted heteroaryl-(Ci-C 3 )alkyl means a
  • heteroaryl-(Ci-C 3 )alkyl functional group in which the heteroaryl group is substituted.
  • heteroaryl or “heteroaromatic” refers to a heterocycle having aromatic character.
  • a polycyclic heteroaryl may include one or more rings that are partially saturated. Examples include the following moieties:
  • heteroaryl groups also include pyridyl, pyrazinyl, pyrimidinyl (particularly 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl (particularly 2-pyrrolyl), imidazolyl, thiazolyl, oxazolyl, pyrazolyl (particularly 3- and 5-pyrazolyl), isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.
  • polycyclic heterocycles and heteroaryls examples include indolyl (particularly 3-, 4-, 5-, 6- and 7-indolyl), indolinyl, quinolyl, tetrahydroquinolyl, isoquinolyl (particularly 1- and 5-isoquinolyl), 1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl (particularly 2- and 5-quinoxalinyl), quinazolinyl, phthalazinyl,
  • 1,2-benzisoxazolyl benzothienyl (particularly 3-, 4-, 5-, 6-, and 7-benzothienyl), benzoxazolyl, benzothiazolyl (particularly 2-benzothiazolyl and 5-benzothiazolyl), purinyl, benzimidazolyl (particularly 2-benzimidazolyl), benzotriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrrolizidinyl, and quinolizidinyl.
  • substituted means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group.
  • substituted further refers to any level of substitution, namely mono-, di-, tri-, tetra-, or penta-substitution, where such substitution is permitted.
  • the substituents vary in number between one and four. In another embodiment, the substituents vary in number between one and three. In yet another embodiment, the substituents vary in number between one and two.
  • the term "optionally substituted” means that the referenced group may be substituted or unsubstituted. In one embodiment, the referenced group is optionally substituted with zero substituents, i.e., the referenced group is unsubstituted. In another embodiment, the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from groups described herein.
  • the substituents are independently selected from the group consisting of oxo, halogen, -CN, - H2, -OH, - H(CH3), -N(CH3)2, alkyl
  • the substituents are independently selected from the group consisting of Ci-6 alkyl, -OH, Ci-6 alkoxy, halo, amino, acetamido, oxo and nitro. In yet another embodiment, the substituents are independently selected from the group consisting of Ci-6 alkyl, Ci-6 alkoxy, halo, acetamido, and nitro. As used herein, where a substituent is an alkyl or alkoxy group, the carbon chain may be branched, straight or cyclic, with straight being preferred.
  • an "instructional material” includes a publication, a recording, a diagram, or any other medium of expression which can be used to
  • the instructional material of the kit of the invention may, for example, be affixed to a container which contains the nucleic acid, peptide, and/or composition of the invention or be shipped together with a container which contains the nucleic acid, peptide, and/or composition.
  • the instructional material may be shipped separately from the container with the intention that the instructional material and the compound be used cooperatively by the recipient.
  • parenteral administration of an immunogenic composition includes, e.g., subcutaneous (s.c), intravenous (i.v.), intramuscular (i.m.), or intrasternal injection, or infusion techniques.
  • subject refers to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein.
  • patient, subject or individual is a human.
  • treatment is defined as the application or administration of a therapeutic agent, i.e., a compound of the invention (alone or in combination with another pharmaceutical agent), to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient (e.g., for diagnosis or ex vivo applications), who has a disease or disorder contemplated herein, a sign or symptom of a disease or disorder contemplated herein or the potential to develop a disease or disorder contemplated herein, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect a diseaser or disorder contemplated herein, at least one sign or symptom of a disease or disorder contemplated herein or the potential to develop a disease or disorder contemplated herein.
  • Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics.
  • ranges throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.
  • the present invention is based on the unexpected discovery that size- expanded DNA (xDNA), also referred to as expanded-size DNA, analogs are efficiently used by ⁇ as substrates and inhibit the DNA synthesis activity of ⁇ .
  • xDNA size- expanded DNA
  • dxNMPs which contain a benzene ring within the base moiety of each nucleoside inhibit ⁇ after two consecutive or closely spaced dxNMP incorporation events.
  • kinetics experiments reveal ⁇ efficiency for dxGMP incorporation closely approaches that of native dGMP.
  • the present invention provides methods and compositions for inhibiting ⁇ in vitro and in vivo.
  • the method comprises administering to a subject an effective amount of a composition comprising an xDNA, an xDNA analog, an xDNA prodrug, or a combination thereof.
  • ⁇ is highly expressed in cancer cells, confers resistance to ionizing radiation and chemotherapy agents, promotes the survival of cancer cells deficient in homologous recombination (HR). High ⁇ expression levels also correspond to a poor clinical outcome for cancer patients.
  • another aspect of the invention provides a method of treating cancer in a subject by administering a composition of the invention.
  • the method comprises administering a composition comprising an xDNA, an xDNA analog, an xDNA prodrug, or a combination thereof.
  • the cancer is resistant to at least one radiation or chemotherapy agent.
  • the cancer is breast cancer.
  • the cancer is ovarian cancer.
  • the cancer is prostate cancer.
  • the invention provides compounds useful for treating cancer.
  • the compounds of the present invention may be synthesized using techniques well-known in the art of organic synthesis.
  • the starting materials and intermediates required for the synthesis may be obtained from commercial sources or synthesized according to methods known to those skilled in the art.
  • the compound of the invention is a compound of Formula (I), or a salt thereof:
  • A is an optionally substituted 4 to 6 membered aromatic or heteroaromatic ring
  • each occurrence of X 1 is independently selected from the group consisting of CR 19 , and N;
  • R 11 to R 15 are each independently selected from the group consisting of H, Fl, CI, Br, I, - R 19 R 110 , -OH, Ci-Ce alkyl, substituted Ci-Ce alkyl, Ci-Ce alkenyl, substituted Ci-C 6 alkenyl, Ci-C 6 alkynyl, substituted Ci-C 6 alkynyl, aiyl, substituted aiyl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -(Ci-Ce)alkyl-phenyl, -(Ci-C6)alkyl-substituted phenyl, -(Ci-C6)alkyl-carbocyclyl, -(Ci-C6)alkyl-heteroaryl, and -(Ci-C6)alkyl-substituted heteroaryl;
  • R 16 is selected from the group consisting of OH, -N 3 , F, CI, and H;
  • each occurrence of R 17 and R 18 is independently selected from the group consisting of H, - R 19 R 110 , -OR 19 , -O " , Ci-Ce alkyl, substituted Ci-Ce alkyl, aryl, substituted aryl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -(Ci-Ce)alkyl-phenyl, substituted -(Ci- C 6 )alkyl- phenyl, -(Ci-C6)alkyl-carbocyclyl, -(Ci-C6)alkyl-heteroaryl, and substituted -(Ci-Ce)alkyl- heteroaryl;
  • X is selected from the group consisting of O, and R 19 ;
  • each occurrence of R 19 is independently is selected from the group consisting of H, N(R 110 )(R 1 U ), Ci-Ce alkyl, substituted Ci-Ce alkyl, aryl, substituted aryl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -(Ci-Ce)alkyl-phenyl, substituted -(Ci-Ce)alkyl- phenyl, -(Ci-C6)alkyl-carbocyclyl, -(Ci-C6)alkyl-heteroaryl, and substituted -(Ci-Ce)alkyl- heteroaryl;
  • each occurrence of R 110 and R 111 is independently is selected from the group consisting of H, Ci-Ce alkyl, substituted Ci-Ce alkyl, aryl, substituted aryl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -(Ci-Ce)alkyl-phenyl, substituted -(Ci-Ce)alkyl- phenyl, -(Ci-C6)alkyl-carbocyclyl, -(Ci-C6)alkyl-heteroaryl, and substituted -(Ci-Ce)alkyl- heteroaryl; and
  • n is an integer from 0-3.
  • A is benzene
  • two occurrences of X 1 are N.
  • the compound of Formula (I) is represented by
  • Ci-Ce alkyl substituted Ci-Ce alkyl, Ci-Ce alkenyl, substituted Ci-C 6 alkenyl, Ci-C 6 alkynyl, substituted Ci-C 6 alkynyl, aiyl, substituted aiyl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -(Ci-Ce)alkyl-phenyl, -(Ci-C6)alkyl-substituted phenyl,
  • R 16 is selected from the group consisting of OH, -N 3 , F, CI, and H;
  • each occurrence of R and R is independently selected from the group consisting of H, - R 19 R 110 , -OR 19 , -O " , Ci-Ce alkyl, substituted Ci-Ce alkyl, aiyl, substituted aiyl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -(Ci-Ce)alkyl-phenyl, substituted -(Ci- C 6 )alkyl- phenyl, -(Ci-C6)alkyl-carbocyclyl, -(Ci-C6)alkyl-heteroaryl, and substituted -(Ci-Ce)alkyl- heteroaryl;
  • X is selected from the group consisting of O, and R 19 ;
  • each occurrence of R 19 and R 110 is independently is selected from the group consisting of H, Ci-Ce alkyl, substituted C1-G5 alkyl, aiyl, substituted aiyl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -(Ci-Ce)alkyl-phenyl, substituted -(Ci-Ce)alkyl- phenyl, -(Ci-C6)alkyl-carbocyclyl, -(Ci-C6)alkyl-heteroaryl, and substituted -(Ci-Ce)alkyl- heteroaryl; and
  • n is an integer from 0-3.
  • R 13 is selected from the group consisting of OH and H 2 .
  • R 14 is - R 19 R 110 .
  • R 19 is H.
  • R 110 is H.
  • R 17 is a substituted Ci-C 6 alkyl. In one embodiment, R 17 is propan-2-yl 2-aminopropanoate.
  • R 18 is H. In one embodiment, R 18 is phenyl.
  • the compound of Formula (I) is selected from the
  • the compound of the invention is a compound of Formula (II), or a salt thereof:
  • R 21 to R 25 are each independently selected from the group consisting of H, Fl, CI, Br, I, - R 29 R 210 , -OH, Ci-Ce alkyl, substituted Ci-Ce alkyl, Ci-Ce alkenyl, substituted Ci-C 6 alkenyl, Ci-C 6 alkynyl, substituted Ci-C 6 alkynyl, aryl, substituted aryl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -(Ci-Ce)alkyl-phenyl, -(Ci-C6)alkyl-substituted phenyl, -(Ci-C6)alkyl-carbocyclyl, -(Ci-C6)alkyl-heteroaryl, and -(Ci-C6)alkyl-substituted heteroaryl
  • R 26 is selected from the group consisting of OH, -N 3 , F, CI, and H;
  • each occurrence of R 27 and R 28 is independently selected from the group consisting of H, - R 29 R 210 , -OR 29 , -O " , Ci-Ce alkyl, substituted Ci-Ce alkyl, aryl, substituted aryl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -(Ci-Ce)alkyl-phenyl, substituted -(Ci- C 6 )alkyl- phenyl, -(Ci-C6)alkyl-carbocyclyl, -(Ci-C6)alkyl-heteroaryl, and substituted -(Ci-Ce)alkyl- heteroaryl;
  • X 1 is selected from the group consisting of O, and R 29 ;
  • X 2 is selected from the group consisting of O, and S;
  • each occurrence of R 29 and R 210 is independently is selected from the group consisting of H, Ci-Ce alkyl, substituted C1-G5 alkyl, aryl, substituted aryl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -(Ci-Ce)alkyl-phenyl, substituted -(Ci-Ce)alkyl- phenyl, substituted -(Ci-Ce)alkyl- phenyl,
  • n is an integer from 0-3.
  • X 2 is O.
  • R 24 is - R 29 R 210 one embodiment, R 29 is H. In one embodiment, R 210 is
  • R 27 is a substituted Ci-C 6 alkyl. In one embodiment, R 27 is propan-2-yl 2-aminopropanoate.
  • R 28 is H. In one embodiment, R 28 is phenyl. In one embodiment, the compound of formula (II) is
  • the compound of the invention is a compound of Formula (III), or a salt thereof:
  • R 31 to R 35 are each independently selected from the group consisting of H, Fl, CI, Br, I, - R 39 R 310 , -OH, Ci-Ce alkyl, substituted Ci-Ce alkyl, Ci-Ce alkenyl, substituted Ci-C 6 alkenyl, Ci-C 6 alkynyl, substituted Ci-C 6 alkynyl, aiyl, substituted aiyl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -(Ci-Ce)alkyl-phenyl, -(Ci-C6)alkyl-substituted phenyl,
  • R 36 is selected from the group consisting of OH, -N 3 , F, CI, and H;
  • each occurrence of R 37 and R 38 is independently selected from the group consisting of H, - R 39 R 310 , -OR 39 , -O " , Ci-Ce alkyl, substituted Ci-Ce alkyl, aiyl, substituted aiyl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -(Ci-Ce)alkyl-phenyl, substituted -(Ci- C 6 )alkyl- phenyl, -(Ci-C6)alkyl-carbocyclyl, -(Ci-C6)alkyl-heteroaryl, and substituted -(Ci-C 6 )alkyl- heteroaryl;
  • X 1 is selected from the group consisting of O, and NR 39 ;
  • X 3 is selected from the group consisting of O and S;
  • each occurrence of R 39 and R 310 is independently is selected from the group consisting of H, Ci-Ce alkyl, substituted Ci-Ce alkyl, aiyl, substituted aiyl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -(Ci-C6)alkyl-phenyl, substituted -(Ci-Ce)alkyl- phenyl, -(Ci-C6)alkyl-carbocyclyl, -(Ci-C6)alkyl-heteroaryl, and substituted -(Ci-Ce)alkyl- heteroaryl; and
  • n is an integer from 0-3.
  • R 34 is H.
  • R 35 is H.
  • R 37 is a substituted Ci-C 6 alkyl.
  • R 27 is propan-2-yl 2-aminopropanoate.
  • R 38 is H. In one embodiment R 38 is phenyl.
  • the compound of formula (III) is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound of the invention is a compound of Formula (IV), or a salt thereof:
  • B is an optionally substituted 4 to 6 membered aromatic or heteroaromatic ring
  • X is selected from the group consisting of O, and R 49 ;
  • X I is selected from the group consisting of N and CR 49 ,
  • X 2 is selected from the group consisting of O, S, NR 49 , and C(R 49 )(R 410 )
  • X 3 is selected from the group consisting of O and S;
  • R 41 to R 45 are each independently selected from the group consisting of H, Fl, CI,
  • Ci-Ce alkyl substituted Ci-Ce alkyl, Ci-Ce alkenyl, substituted Ci- C 6 alkenyl, Ci-Ce alkynyl, substituted C1-G5 alkynyl, aiyl, substituted aiyl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -(Ci-Ce)alkyl-phenyl, -(Ci-C6)alkyl-substituted phenyl, -(Ci-Ce)alkyl- carbocyclyl, -(Ci-C6)alkyl-heteroaryl, and -(Ci-C6)alkyl-substituted heteroaryl;
  • each occurrence of R 47 and R 48 is independently selected from the group consisting of H, - R 49 R 410 , -OR 49 , -O " , Ci-Ce alkyl, substituted Ci-Ce alkyl, aiyl, substituted aiyl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -(Ci-Ce)alkyl-phenyl, substituted -(Ci- C 6 )alkyl- phenyl, -(Ci-C6)alkyl-carbocyclyl, -(Ci-C6)alkyl-heteroaryl, and substituted -(Ci-Ce)alkyl- heteroaryl;
  • each occurrence of R 49 and R 410 is independently is selected from the group consisting of H, C1-G5 alkyl, substituted C1-G5 alkyl, aiyl, substituted aiyl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -(Ci-Ce)alkyl-phenyl, substituted -(Ci-Ce)alkyl- phenyl, -(Ci-Ce)alkyl- carbocyclyl, -(Ci-C6)alkyl-heteroaryl, and substituted -(Ci-Ce)alkyl- heteroaryl; and
  • n is an integer from 0-3.
  • B is selected from the group consisting of benzene, pyridine, cyclobutadiene, furan, and thiophene, wherein B is optionally substituted.
  • the compound of Formula (IV) is a compound of
  • R 41 to R 45 are each independently selected from the group consisting of H, Fl, CI, Br, I, - R 49 R 410 , -OH, Ci-Ce alkyl, substituted Ci-Ce alkyl, Ci-Ce alkenyl, substituted Ci- C 6 alkenyl, Ci-Ce alkynyl, substituted Ci-C 6 alkynyl, aiyl, substituted aiyl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -(Ci-C6)alkyl-phenyl, -(Ci-C6)alkyl-substituted phenyl, -(Ci-Ce)alkyl- carbocyclyl, -(Ci-C6)alkyl-heteroaryl, and -(Ci-C6)alkyl-substituted heteroaryl;
  • R 46 is selected from the group consisting of OH, -N 3 , F, CI, and H;
  • each occurrence of R 47 and R 48 is independently selected from the group consisting of H, - R 49 R 410 , -OR 49 , -O " , Ci-Ce alkyl, substituted Ci-Ce alkyl, aryl, substituted aryl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -(Ci-Ce)alkyl-phenyl, substituted -(Ci- C 6 )alkyl- phenyl, -(Ci-C6)alkyl-carbocyclyl, -(Ci-C6)alkyl-heteroaryl, and substituted -(Ci-Ce)alkyl- heteroaryl;
  • X is selected from the group consisting of O, and R 49 ;
  • each occurrence of R 49 and R 410 is independently is selected from the group consisting of H, Ci-Ce alkyl, substituted Ci-Ce alkyl, aryl, substituted aryl, carbocyclyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, -(Ci-Ce)alkyl-phenyl, substituted -(Ci-Ce)alkyl- phenyl, -(Ci-Ce)alkyl- carbocyclyl, -(Ci-C6)alkyl-heteroaryl, and substituted -(Ci-Ce)alkyl- heteroaryl; and n is an integer from 0-3.
  • R 44 is H.
  • each occurrence of R 45 is H.
  • R 47 is a substituted Ci-C 6 alkyl. In one embodiment, R is propan-2-yl 2-aminopropanoate.
  • R 48 is H. In one embodiment, R 48 is phenyl.
  • the compound of Formula (IV) is selected from the
  • the compounds of the invention may possess one or more stereocenters, and each stereocenter may exist independently in either the R or S configuration.
  • compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds described herein encompass racemic, optically-active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein.
  • the sugar moiety of the compound of the invention comprises the stereochemistry of
  • optically active forms are achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase.
  • a mixture of one or more isomer is utilized as the therapeutic compound described herein.
  • compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including
  • stereoselective synthesis, enantioselective synthesis and/or separation of a mixture of enantiomers and/ or diastereomers Resolution of compounds and isomers thereof is achieved by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.
  • N oxides if appropriate
  • crystalline forms also known as polymorphs
  • solvates amorphous phases
  • pharmaceutically acceptable salts include water, ether (e.g., tetrahydrofuran, methyl tert-butyl ether) or alcohol (e.g., ethanol) solvates, acetates and the like.
  • the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, and ethanol.
  • the compounds described herein exist in unsolvated form.
  • the compounds of the invention may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.
  • prodrugs In one embodiment, compounds described herein are prepared as prodrugs.
  • a "prodrug” refers to an agent that is converted into the parent drug in vivo.
  • a prodrug upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound.
  • a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.
  • sites on, for example, the aromatic ring portion of compounds of the invention are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the aromatic ring structures may reduce, minimize or eliminate this metabolic pathway. In one embodiment, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a deuterium, a halogen, or an alkyl group.
  • Compounds described herein also include isotopically-labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds described herein include and are not limited to 2H, 3H, 11C, 13C, 14C, 36C1, 18F, 1231, 1251, 13N, 15N, 150, 170, 180, 32P, and 35S.
  • isotopically-labeled compounds are useful in drug and/or substrate tissue distribution studies.
  • substitution with heavier isotopes such as deuterium affords greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements).
  • substitution with positron emitting isotopes, such as 11C, 18F, 150 and 13N is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • Isotopically-labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically-labeled reagent in place of the non- labeled reagent otherwise employed.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • reactive functional groups such as hydroxyl, amino, imino, thio or carboxy groups, are protected in order to avoid their unwanted
  • Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed.
  • each protective group is removable by a different means.
  • Protective groups that are cleaved under totally disparate reaction conditions fulfill the requirement of differential removal.
  • protective groups are removed by acid, base, reducing conditions (such as, for example, hydrogenolysis), and/or oxidative conditions.
  • reducing conditions such as, for example, hydrogenolysis
  • oxidative conditions such as, for example, hydrogenolysis
  • Groups such as trityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labile and are used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile.
  • Carboxylic acid and hydroxy reactive moieties are blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl, in the presence of amines that are blocked with acid labile groups, such as t-butyl carbamate, or with carbamates that are both acid and base stable but hydrolytically removable.
  • base labile groups such as, but not limited to, methyl, ethyl, and acetyl
  • carboxylic acid and hydroxy reactive moieties are blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups capable of hydrogen bonding with acids are blocked with base labile groups such as Fmoc.
  • Carboxylic acid reactive moieties are protected by conversion to simple ester compounds as exemplified herein, which include conversion to alkyl esters, or are blocked with oxidatively-removable protective groups such as 2,4
  • Allyl blocking groups are useful in the presence of acid- and base- protecting groups since the former are stable and are subsequently removed by metal or pi-acid catalysts.
  • an allyl-blocked carboxylic acid is deprotected with a palladium-catalyzed reaction in the presence of acid labile t-butyl carbamate or base- labile acetate amine protecting groups.
  • Yet another form of protecting group is a resin to which a compound or intermediate is attached. As long as the residue is attached to the resin, that functional group is blocked and does not react. Once released from the resin, the functional group is available to react.
  • blocking/protecting groups may be selected from:
  • the invention is based, in part, on the discovery that ⁇ efficiently incorporates expanded-size DNA (xDNA)
  • xDNA nucleosides and nucleotides, xDNA nucleoside and nucleotide analogs and xDNA nucleotide and nucleoside prodrugs are useful therapeutics for treating cancer.
  • the invention provides an inhibitor of ⁇ .
  • the present invention includes compositions for inhibiting the DNA synthesis activity of ⁇ in a subject, a tissue, or an organ in need thereof.
  • the composition comprises an expanded-size DNA (xDNA) or an analog thereof.
  • xDNA which include a benzene ring within the base moiety of each canonical nucleoside.
  • the xDNA binds to ⁇ .
  • ⁇ catalyzes the incorporation of a first xDNA.
  • the composition comprises at least one compound represented by one of Formulae (I) to (IV).
  • ⁇ is highly upregulated in multiple cancer types and corresponds to a poor survival rate for breast cancer patients. ⁇ has also been shown to confer resistance to ionizing radiation and other chemotherapy agents such as Olaparib.
  • the invention provides a generic concept for inhibiting ⁇ as an anti-cancer therapy.
  • the composition comprises an expanded-size DNA (xDNA) or an analog thereof. xDNA which include a benzene ring within the base moiety of each canonical nucleoside.
  • the xDNA binds to ⁇ .
  • ⁇ catalyzes the incorporation of a first xDNA nucleotide.
  • the composition comprises at least one compound represented by one of Formulae (I) to (IV).
  • the invention provides methods of treating or preventing cancer, or of treating and preventing metastasis of tumors.
  • Related aspects of the invention provide methods of inhibiting ⁇ in a subject, a tissue, or an organ in need thereof.
  • One aspect of the invention provides a method of treating cancer in an individual in need thereof, the method comprising administering to the individual an effective amount of a composition comprising at least one compound of Formulae (I) to (IV).
  • the invention further provides a method of inhibiting ⁇ in an individual in need thereof, the method comprising administering to the individual an effective amount of any one of the compositions described herein.
  • the invention provides a method of treating cancer in a subject comprising administering to the subject an effective amount of a composition comprising at least one compound of Formulae (I) to (IV).
  • the cancer is resistant to at least radiation or chemotherapy agent.
  • the cancer is breast cancer.
  • the cancer is ovarian cancer.
  • the cancer is ovarian cancer.
  • the disclosed compounds can be used to slow the rate of primary tumor growth.
  • the disclosed compounds can also be used to prevent, abate, minimize, control, and/or lessen tumor metastasis in humans and animals.
  • the disclosed compounds when administered to a subject in need of treatment can be used to stop the spread of cancer cells.
  • the compounds disclosed herein can be administered as part of a combination therapy with one or more drugs or other pharmaceutical agents.
  • the decrease in metastasis and reduction in primary tumor growth afforded by the disclosed compounds allows for a more effective and efficient use of any pharmaceutical or drug therapy being used to treat the patient.
  • control of metastasis by the disclosed compound affords the subject a greater ability to concentrate the disease in one location.
  • cancers that can be treated by the disclosed methods and compositions: Acute Lymphoblastic; Acute Myeloid
  • Ependymoma Medulloblastoma; Medulloepithelioma; Pineal Parenchymal Tumors of intermediate Differentiation; Supratentorial Primitive Neuroectodermal Tumors and Pineoblastoma; Visual Pathway and Hypothalamic Glioma; Brain and Spinal Cord Tumors; Breast Cancer; Bronchial Tumors; Burkitt Lymphoma; Carcinoid Tumor;
  • Gallbladder Cancer Gastric (Stomach) Cancer; Gastrointestinal Carcinoid Tumor;
  • Gastrointestinal Stromal Tumor GIST
  • Germ Cell Tumor Extracranial
  • Germ Cell Tumor Extragonadal
  • Germ Cell Tumor Ovarian
  • Gestational Trophoblastic Tumor Glioma
  • Glioma Childhood Brain Stem
  • Glioma Childhood Cerebral Astrocytoma
  • Glioma Childhood Visual Pathway and Hypothalamic; Hairy Cell Leukemia; Head and Neck Cancer; Hepatocellular (Liver) Cancer; Histiocytosis, Langerhans Cell; Hodgkin Lymphoma; Hypopharyngeal Cancer; Hypothalamic and Visual Pathway Glioma;
  • Introcular Melanoma Introcular Melanoma; Islet Cell Tumors; Kidney (Renal Cell) Cancer; Langerhans Cell Histiocytosis; Laryngeal Cancer; Leukemia, Acute Lymphoblastic; Leukemia, Acute
  • Myelogenous Leukemia Chronic; Myeloid Leukemia, Adult Acute; Myeloid Leukemia, Childhood Acute; Myeloma, Multiple; Myeloproliferative Disorders, Chronic; Nasal Cavity and Paranasal Sinus Cancer; Nasopharyngeal Cancer; Neuroblastoma; Non-Small Cell Lung Cancer; Oral Cancer; Oral Cavity Cancer; Oropharyngeal Cancer;
  • Sarcoma Ewing Family of Tumors; Sarcoma, Kaposi; Sarcoma, Soft Tissue; Sarcoma, Uterine; Sezary Syndrome; Skin Cancer (Nonmelanoma); Skin Cancer (Melanoma); Skin Carcinoma, Merkel Cell; Small Cell Lung Cancer; Small Intestine Cancer; Soft Tissue Sarcoma; Squamous Cell Carcinoma, Squamous Neck Cancer with Occult Primary, Metastatic; Stomach (Gastric) Cancer; Supratentorial Primitive Neuroectodermal Tumors; T-Cell Lymphoma, Cutaneous; Testicular Cancer; Throat Cancer; Thymoma and Thymic Carcinoma; Thyroid Cancer; Transitional Cell Cancer of the Renal Pelvis and Ureter; Trophoblastic Tumor, Gestational; Urethral Cancer; Uterine Cancer, Endometrial; Uterine Sarcoma; Vaginal Cancer; Vulvar Cancer; Waldenstrom
  • the method for treating cancer in an subject in need thereof comprises administering an effective amount of a composition comprising at least one compound of Formulae (I) to (IV) to the subject prior to, concurrently with, or subsequently to the treatment with a complementary therapy for the cancer, such as surgery, chemotherapy, chemotherapeutic agent, radiation therapy, or hormonal therapy or a combination thereof.
  • a complementary therapy for the cancer such as surgery, chemotherapy, chemotherapeutic agent, radiation therapy, or hormonal therapy or a combination thereof.
  • Chemotherapeutic agents include cytotoxic agents (e.g., 5-fluorouracil, cisplatin, carboplatin, methotrexate, daunorubicin, doxorubicin, vincristine, vinblastine, oxorubicin, carmustine (BCNU), lomustine (CCNU), cytarabine USP,
  • cytotoxic agents e.g., 5-fluorouracil, cisplatin, carboplatin, methotrexate, daunorubicin, doxorubicin, vincristine, vinblastine, oxorubicin, carmustine (BCNU), lomustine (CCNU), cytarabine USP,
  • cyclophosphamide estramucine phosphate sodium, altretamine, hydroxyurea, ifosfamide, procarbazine, mitomycin, busulfan, cyclophosphamide, mitoxantrone, carboplatin, cisplatin, interferon alfa-2a recombinant, paclitaxel, teniposide, and streptozoci), cytotoxic alkylating agents (e.g., busulfan, chlorambucil, cyclophosphamide, melphalan, or ethylesulfonic acid), alkylating agents (e.g., asaley, AZQ, BCNU, busulfan, bisulphan, carboxyphthalatoplatinum, CBDCA, CCNU, CHIP, chlorambucil, chlorozotocin, cis- platinum, clomesone, cyanomorpholinodoxorubicin, cyclodisone, cyclophospham
  • Antiproliferative agents are compounds that decrease the proliferation of cells.
  • Antiproliferative agents include alkylating agents, antimetabolites, enzymes, biological response modifiers, miscellaneous agents, hormones and antagonists, androgen inhibitors (e.g., flutamide and leuprolide acetate), antiestrogens (e.g., tamoxifen citrate and analogs thereof, toremifene, droloxifene and roloxifene), Additional examples of specific antiproliferative agents include, but are not limited to levamisole, gallium nitrate, granisetron, sargramostim strontium-89 chloride, filgrastim, pilocarpine, dexrazoxane, and ondansetron.
  • the inhibitors of the invention can be administered alone or in combination with other anti -tumor agents, including cytotoxic/antineoplastic agents and anti-angiogenic agents.
  • Cytotoxic/anti-neoplastic agents are defined as agents which attack and kill cancer cells.
  • Some cytotoxic/anti-neoplastic agents are alkylating agents, which alkylate the genetic material in tumor cells, e.g., cis-platin, cyclophosphamide, nitrogen mustard, trimethylene thiophosphoramide, carmustine, busulfan, chlorambucil, belustine, uracil mustard, chlomaphazin, and dacabazine.
  • cytotoxic/anti-neoplastic agents are antimetabolites for tumor cells, e.g., cytosine arabinoside, fluorouracil, methotrexate, mercaptopuirine, azathioprime, and procarbazine.
  • Other cytotoxi ⁇ antineoplastic agents are antibiotics, e.g., doxorubicin, bleomycin, dactinomycin,
  • cytotoxic/anti-neoplastic agents are mitotic inhibitors (vinca alkaloids). These include vincristine, vinblastine and etoposide. Miscellaneous cytotoxic/anti-neoplastic agents include taxol and its derivatives, L-asparaginase, anti-tumor antibodies, dacarbazine, azacytidine, amsacrine, melphalan, VM-26, ifosfamide, mitoxantrone, and vindesine.
  • Anti-angiogenic agents are well known to those of skill in the art. Suitable anti-angiogenic agents for use in the methods and compositions of the present disclosure include anti-VEGF antibodies, including humanized and chimeric antibodies, anti-VEGF aptamers and antisense oligonucleotides. Other known inhibitors of angiogenesis include angiostatin, endostatin, interferons, interleukin 1 (including alpha and beta) interleukin 12, retinoic acid, and tissue inhibitors of metalloproteinase-1 and -2. (TIMP-1 and -2). Small molecules, including topoisom erases such as razoxane, a topoisomerase II inhibitor with anti-angiogenic activity, can also be used.
  • anti-cancer agents that can be used in combination with the disclosed compounds include, but are not limited to: acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedef
  • spirogermanium hydrochloride spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride;
  • temoporfin teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate;
  • vindesine ; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin;
  • anti-cancer drugs include, but are not limited to: 20-epi-l,25 dihy droxy vitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;
  • acylfulvene acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine;
  • anagrelide anastrozole; andrographolide; angiogenesis inhibitors; antagonist D;
  • antagonist G antagonist G; antarelix; anti-dorsalizing morphogenetic protein- 1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-
  • PTBA arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol;
  • batimastat BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate;
  • bropirimine bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole;
  • carboxyamidotriazole CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins;
  • chloroquinoxaline sulfonamide cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4;
  • combretastatin analogue conagenin; crambescidin 816; crisnatol; cryptophycin 8;
  • cryptophycin A derivatives curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane;
  • dexverapamil diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5- azacytidine; dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen;
  • ecomustine ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin;
  • epristeride estramustine analogue
  • estrogen agonists include estrogen agonists, estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; trasrabine; fenretinide; filgrastim;
  • imiquimod immunostimulant peptides; insulin-like growth factor- 1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-
  • iroplact irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide
  • mopidamol multiple drug resistance gene inhibitor; multiple tumor suppressor 1 -based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; 06-benzylguanine; octreotide; okicenone;
  • oligonucleotides onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues;
  • paclitaxel derivatives palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol;
  • hydrochloride pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase
  • C inhibitors microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated;
  • sarcophytol A sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen binding protein; sizofuran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid;
  • spicamycin D spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine;
  • tazarotene tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; t
  • variolin B vector system, erythrocyte gene therapy; velaresol; veramine; verdins;
  • the anti-cancer drug is 5-fluorouracil, taxol, or leucovorin.
  • the regimen of administration may affect what constitutes an effective amount.
  • the therapeutic formulations may be administered to the subject either before or after the onset of cancer. Further, several divided dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection.
  • the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation.
  • compositions of the present invention may be carried out using known procedures, at dosages and for periods of time effective to treat cancer in the patient.
  • An effective amount of the therapeutic compound necessary to achieve a therapeutic effect may vary according to factors such as the state of the disease or disorder in the patient; the age, sex, and weight of the patient; and the ability of the therapeutic compound to treat a cancer in the patient.
  • Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily. In another example, the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • a non-limiting example of an effective dose range for a therapeutic compound of the invention is from about 1 mg/kg to about 5,000 mg/kg of body weight/per day.
  • One of ordinary skill in the art would be able to assess the relevant factors and make the determination regarding the effective amount of the therapeutic compound without undue experimentation.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without generating excessive side effects in the patient.
  • the selected dosage level depends upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts.
  • a medical professional e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • physician or veterinarian could start with a dosage of the compound of the invention in the pharmaceutical composition at a level that is lower than the level required to achieve the desired therapeutic effect, and then increase the dosage over time until the desired effect is achieved.
  • dosage unit form refers to a physically discrete unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect, in association with the required pharmaceutical vehicle.
  • the dosage unit forms of the invention can be selected based upon (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding/formulating such a therapeutic compound for the treatment of cancer in a patient.
  • compositions of the invention are formulated using one or more pharmaceutically acceptable excipients or carriers.
  • compositions of the invention comprise a
  • the carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), vegetable oils, and suitable mixtures thereof .
  • the proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • the composition it is useful to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions can be achieved by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin.
  • the pharmaceutically acceptable carrier is DMSO, alone or in combination with other carriers.
  • the therapeutically effective amount or dose of a compound of the present invention depends on the age, sex and weight of the patient, the current medical condition of the patient and the severity of the cancer in the patient being treated. The skilled artisan is able to determine appropriate doses depending on these and other factors.
  • the dose may be administered in a single dosage or in multiple dosages, for example from 1 to 4 or more times per day.
  • the amount of each dosage may be the same or different.
  • a dose of 1 mg per day may be administered as two 0.5 mg doses, with about a 12-hour interval between doses.
  • Doses of the compound of the invention for administration may be in the range of from about 1 mg to about 10,000 mg, from about 20 mg to about 9,500 mg, from about 40 mg to about 9,000 mg, from about 75 mg to about 8,500 mg, from about 150 mg to about 7,500 mg, from about 200 mg to about 7,000 mg, from about 3050 mg to about 6,000 mg, from about 500 mg to about 5,000 mg, from about 750 mg to about 4,000 mg, from about 1 mg to about 3,000 mg, from about 10 mg to about 2,500 mg, from about 20 mg to about 2,000 mg, from about 25 mg to about 1,500 mg, from about 30 mg to about 1,000 mg, from about 40 mg to about 900 mg, from about 50 mg to about 800 mg, from about 60 mg to about 750 mg, from about 70 mg to about 600 mg, from about 80 mg to about 500 mg, and any and all whole or partial increments there between.
  • the dose of a compound of the invention is from about 1 mg to about 2,500 mg. In some embodiments, a dose of a compound of the invention used in compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg.
  • the dosage of a second compound as described elsewhere herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof.
  • the compounds for use in the method of the invention may be formulated in unit dosage form.
  • unit dosage form refers to physically discrete units suitable as unitary dosage for patients undergoing treatment, with each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier.
  • the unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose.
  • compositions of the invention are administered to the patient from about one to about five times per day or more.
  • the compositions of the invention are administered to the patient, 1-7 times per day, 1-7 times every two days, 1-7 times every 3 days, 1-7 times every week, 1-7 times every two weeks, and 1-7 times per month.
  • the frequency of administration of the various combination compositions of the invention will vary from individual to individual depending on many factors including, but not limited to, age, the disease or disorder to be treated, the severity of the disease or disorder to be treated, gender, overall health, and other factors.
  • the invention should not be construed to be limited to any particular dosing regime and the precise dosage and composition to be administered to any patient is determined by the medical professional taking all other factors about the patient into account.
  • the administration of the inhibitor of the invention is optionally given continuously; alternatively, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug holiday").
  • the length of the drug holiday optionally varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days.
  • the dose reduction during a drug holiday includes from 10%- 100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.
  • a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, may be reduced to a level at which the improved disease is retained. In some embodiments, a patient may require intermittent treatment on a long- term basis, or upon any recurrence of the disease or disorder.
  • Toxicity and therapeutic efficacy of such therapeutic regimens are optionally determined in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index, which is expressed as the ratio between LD50 and ED50.
  • the data obtained from cell culture assays and animal studies are optionally used in formulating a range of dosage for use in human.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity.
  • the dosage optionally varies within this range depending upon the dosage form employed and the route of administration utilized.
  • the present invention is directed to a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound of the invention, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat or prevent cancer in a patient.
  • Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, intravenous, subcutaneous, enteral, or any other suitable mode of administration, known to the art.
  • the pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, coloring, flavoring and/or aromatic substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic agents.
  • routes of administration of any of the compositions of the invention include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical.
  • the compounds for use in the invention may be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.
  • compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral
  • formulations and compositions that would be useful in the present invention are not limited to the particular formulations and compositions that are described herein.
  • suitable forms include tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gelcaps.
  • suitable forms include tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gelcaps.
  • the compositions formulated for oral use may be prepared according to any method known in the art and such
  • compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets.
  • excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate.
  • the tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.
  • the compounds of the invention may be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., polyvinylpyrrolidone,
  • the tablets may be coated using suitable methods and coating materials such as OP ADR YTM film coating systems available from Colorcon, West Point, Pa. (e.g., OP ADR YTM OY Type, OYC Type, Organic Enteric OY- P Type, Aqueous Enteric OY-A Type, OY-PM Type and OP ADR YTM White,
  • Liquid preparation for oral administration may be in the form of solutions, syrups or suspensions.
  • the liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxy benzoates or sorbic acid).
  • suspending agents e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats
  • emulsifying agent e.g., lecithin or acacia
  • non-aqueous vehicles e.g., almond oil, oily esters or ethyl alcohol
  • preservatives e.g., methyl or propyl p-hydroxy benzoates or sorb
  • Granulating techniques are well known in the pharmaceutical art for modifying starting powders or other particulate materials of an active ingredient.
  • the powders are typically mixed with a binder material into larger permanent free-flowing agglomerates or granules referred to as a "granulation.”
  • solvent-using "wet" granulation processes are generally characterized in that the powders are combined with a binder material and moistened with water or an organic solvent under conditions resulting in the formation of a wet granulated mass from which the solvent must then be evaporated.
  • Melt granulation involves the use of materials that are solid or semi-solid at room temperature (i.e., having a relatively low softening or melting point range) to promote granulation of powdered or other materials, essentially in the absence of added water or other liquid solvents.
  • the low melting solids when heated to a temperature in the melting point range, liquefy to act as a binder or granulating medium.
  • the liquefied solid spreads itself over the surface of powdered materials with which it is contacted, and on cooling, forms a solid granulated mass in which the initial materials are bound together.
  • the resulting melt granulation may then be provided to a tablet press or be encapsulated for preparing the oral dosage form.
  • Melt granulation improves the dissolution rate and bioavailability of an active (i.e., drug) by forming a solid dispersion or solid solution.
  • U.S. Patent No. 5, 169,645 discloses directly compressible wax-containing granules having improved flow properties.
  • the granules are obtained when waxes are admixed in the melt with certain flow improving additives, followed by cooling and granulation of the admixture.
  • certain flow improving additives such as sodium bicarbonate
  • only the wax itself melts in the melt combination of the wax(es) and additives(s), and in other cases both the wax(es) and the additives(s) melt.
  • the present invention also includes a multi-layer tablet comprising a layer providing for the delayed release of one or more compounds of the invention, and a further layer providing for the immediate release of a medication for treatment of G- protein receptor-related diseases or disorders.
  • a gastric insoluble composition may be obtained in which the active ingredient is entrapped, ensuring its delayed release.
  • the compounds of the invention may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose and/or continuous infusion.
  • Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing and/or dispersing agents may be used.
  • Additional dosage forms of this invention include dosage forms as described in U.S. Patents Nos. 6,340,475; 6,488,962; 6,451,808; 5,972,389; 5,582,837; and 5,007,790. Additional dosage forms of this invention also include dosage forms as described in U.S. Patent Applications Nos. 20030147952; 20030104062; 20030104053;
  • the formulations of the present invention may be, but are not limited to, short-term, rapid-offset, as well as controlled, for example, sustained release, delayed release and pulsatile release formulations.
  • sustained release refers to a drug formulation that provides for gradual release of a drug over an extended period of time, and that may, although not necessarily, result in substantially constant blood levels of a drug over an extended time period.
  • the period of time may be as long as a day, a week, or a month or more and should be a release which is longer that the same amount of agent administered in bolus form.
  • delayed release is used herein in its conventional sense to refer to a drug formulation that provides for an initial release of the drug after some delay following drug administration and that mat, although not necessarily, includes a delay of from about 10 minutes up to about 12 hours.
  • the compounds may be formulated with a suitable polymer or hydrophobic material which provides sustained release properties to the compounds.
  • the compounds for use the method of the invention may be administered in the form of microparticles, for example, by injection or in the form of wafers or discs by implantation.
  • the compounds of the invention are administered to a patient, alone or in combination with another pharmaceutical agent, using a sustained release formulation.
  • pulsatile release refers to a drug formulation that provides release of the drug in such a way as to produce pulsed plasma profiles of the drug after drug administration.
  • immediate release refers to a drug formulation that provides for release of the drug immediately after drug administration.
  • short-term refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes and any or all whole or partial increments thereof after drug administration after drug administration.
  • rapid-offset refers to any period of time up to and including about 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20 minutes, or about 10 minutes, and any and all whole or partial increments thereof after drug administration.
  • reaction conditions including but not limited to reaction times, reaction size/volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing/oxidizing agents, with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application.
  • ⁇ efficiently and selectively incorporates into DNA large benzo-expanded nucleotide analogs (dxAMP, dxGMP, dxTMP, dxAMP) which exhibit canonical base-pairing and enhanced base stacking.
  • functionally related Y-family translesion polymerases exhibit a severely reduced ability to incorporate dxNMPs, and X- and B-family polymerases fail to incorporate them.
  • ⁇ is inhibited after two consecutive dxNMP incorporation events, and surprisingly, kinetics experiments reveal ⁇ efficiency for dxGMP incorporation approaching that of native dGMP.
  • Primer extension was performed by incubating 90 nM of the indicated polymerase with 100 nM of indicated radio-labeled or cy3-labeled primer-template in the presence of the indicated nucleotides at 37° C in the following buffer: 25 mM TrisHCl pH 8.8, 10 mM MgC12, 0.1 mg/ml BSA, 0.01% P-40, 5 mM DTT, 10% glycerol.
  • Reactions were performed for 30 min unless noted otherwise. Reactions were terminated by the addition of 2X stop buffer (50 mM EDTA, 90% formamide). DNA products were resolved in denaturing urea polyacrylamide gels and visualized by autoradiography for radio-labeled DNA or fluorescence scanning for cy3 -labeled DNA. Percent extension was determined by dividing the intensity of the bands representing the extension products by the sum of the intensity of the bands representing initial and extended products.
  • Reactions were initiated by the addition of dGTP or dxGTP at indicated concentrations and terminated after 2 min by the addition of 2X stop buffer (50 mM EDTA, 90% formamide). Reaction products were resolved in denaturing urea polyacrylamide gels and visualized by autoradiography. Multiple films were generated under variable exposure times to ensure bands were not overexposed. Percent extension was determined by dividing the intensity of the extended products by the sum of the intensities of the unextended and extended products. Image J was used to quantify the intensities of radio-labeled DNA. Reactions were performed in triplicate and average velocities for each nucleotide concentration were determined. The substrate (nucleotide) concentrations were regarded as constant throughout the reaction. The data were fit to Hanes-Woolf plots which were used to determine the relative Vmax and K m for each nucleotide.
  • Human ⁇ , ⁇ and ⁇ were purified as described (Kent et al., 2015, Nat Struct Mol biol 22:230-7). Exonuclease deficient human ⁇ was purified as described(Kasiviswanathan et al., 2012, J Biol Chem 287:9222-9). Human Pols ⁇ and ⁇ were purchased from Enzymax.
  • Primer-templates were annealed by mixing together a 2: 1 ratio of template strand to primer strand followed by heating to 95-100° C then slowly cooling to room temp.
  • Primer strand was radio-labeled by using bacteriophage T4 polynucleotide kinase (New England Biolabs) in the presence of 32 ⁇ - ⁇ - ⁇ (Perkin Elmer). In some instances a Cy3 5' labeled RP25 primer strand was used as indicated.
  • the following primer- template pairs (primer/template) are shown in table 2. Table 3 depicts the sequences of the primers and templates.
  • Canonical dNTPs were purchased from Promega. Expanded-size synthesized as described (Jarchow-Choy et al., 2011, NAR 39: 1586-94).
  • ⁇ demonstrated efficient use of all four dxNTPs as substrates for primer-template extension ( Figures IB-IE).
  • ⁇ exhibited a similar efficiency of primer-template extension in the presence of the complementary dNTP or dxNTP for each template ( Figures IB- IE).
  • the slowed mobility of the extended primer in the presence of the dxCTP compared to dCTP is consistent with the slightly higher molecular weight of the size-expanded nucleoside (dxCMP) ( Figure IB).
  • ⁇ further extends a fraction of the primers due to misincorporation of dxCMP opposite the next template base, adenine (A) ( Figure IB).
  • Y-family translesion polymerases exhibit a limited ability to incorporate dx MPs
  • X-family polymerases perform gap filling during non-homologous end-joining (NHEJ) and base excision repair (BER). Overall, X-family polymerases exhibit a relatively high error rate (10 ⁇ 2 to 10 "4 ) compared to B-family replicative polymerases ( ⁇ 10 ⁇ 5 ) which also exhibit exonuclease activity for proofreading misincorporation errors (McCulloch and Kunkel, 2008, Cell Res 18: 148-61; Yamtich and Sweasy, 2010, Biochim Biophys Acta 1804: 1136-50).
  • X-family polymerases are more accurate than Y-family polymerases which exhibit relatively high error rates (10 ⁇ 2 to 10 "3 ) on undamaged DNA (McCulloch and Kunkel, 2008, Cell Res 18: 148-61; Yamtich and Sweasy, 2010, Biochim Biophys Acta 1804: 1136-50). Consistent with its higher fidelity than Y-family polymerases, ⁇ exhibited a substantially lower efficiency of dxNMP incorporation (0.2 - 12% extension) compared to Pols ⁇ and ⁇ (0.5 - 40% extension) (compare Figure 2 and Figure 3).
  • ⁇ failed to incorporate dxCMP and dxTTP and showed only a very slight ability to incorporate dxGMP and dxAMP during the 30 minute time course ( Figure 3). Because ⁇ performs gap filling during base excision repair, its ability to incorporate purine and pyrimidine based dxNMPs was examined on a primer- template substrate containing a small gap with a 5' phosphate on the oligonucleotide downstream from the primer. On this substrate ⁇ failed to incorporate dxCMP and showed only a small increase in dxGMP incorporation (Figures 3E and 3F). X-family ⁇ also failed to effectively use dxNTPs as substrates like ⁇ ( Figure 7). Thus, these data demonstrate that X-family polymerases strongly select against size-expanded nucleotides.
  • dxNMPs were investigated. These enzymes are responsible for replicating the genome in eukaryotes and therefore exhibit relatively high fidelities of nucleotide incorporation. For example, ⁇ and ⁇ were shown to exhibit error rates less than 10 "5 (McCulloch and Kunkel, 2008, Cell Res 18: 148-61). ⁇ and ⁇ possess proofreading activity which contributes to these low error rates. In order to examine the incorporation of dxNMPs by ⁇ and ⁇ it was necessary to devise a slightly different experimental method due to their robust exonuclease activities which are stimulated when one or more nucleotides are omitted from the reaction.
  • primer-template extension assay which limits the exonuclease activities of ⁇ and ⁇ while detecting their ability to incorporate dxNMPs.
  • all four nucleotides were added to the reaction; however, dGTP was replaced with dxGTP.
  • dGTP was replaced with dxGTP.
  • these high-fidelity enzymes are capable of efficient incorporation of dxNMPs, full primer extension and little or no exonuclease activity should be observed.
  • these enzymes are unable to efficiently incorporate dxNMPs, their respective exonuclease activities should be activated at the cytosine template base located immediately downstream from the 3' terminus of the primer.
  • B-family Pola which functions as a replicative primase, selected against incorporating size-expanded nucleotides.
  • Pola lacks exonuclease activity and therefore may incorporate dxNMPs during a prolonged incubation time of 30 minutes.
  • the results show that Pola fails to incorporate purine and pyrimidine based dxNMPs like Pols ⁇ and ⁇ .
  • the mitochondrial replicative ⁇ which is also an A-family member, may similarly use size-expanded nucleotides as substrates. This could conceivably cause toxicity in patients treated with prodrug chain terminator versions of size-expanded nucleotide or nucleoside analogs.
  • the ability of an exonuclease deficient mutant version of ⁇ to incorporate purine and pyrimidine versions of dx MPs was tested ( Figure 4E).
  • the related Pol D fails to use purine and pyrimidine based dxNTPs as substrates under identical conditions (Fig. 4E).
  • the data presented insofar demonstrate that ⁇ exhibits a unique ability to utilize dxNTPs as substrates and suggest that chain terminator versions of size-expanded nucleotides could be developed as specific inhibitors of ⁇ .
  • ⁇ is inhibited after multiple dx MP incorporation events
  • Previous studies have demonstrated that ⁇ exhibits a relatively high efficiency of mismatch extension (Seki and Wood, 2008, DNA Repair 7: 119-27). This suggests that ⁇ may also efficiently extend from a dxNMP located at the 3' primer terminus.
  • ⁇ was incubated with the primer-template in the presence of dxCTP to allow for nearly full incorporation of the nucleotide ( Figure 5 A, left panel, lane 2).
  • Figure 5 A left panel, lane 2
  • To assess whether ⁇ is capable of efficiently extending from the incorporated dxCMP the reaction was repeated, however, all 4 canonical dNTPs were added after the initial 15 min incubation with dxCTP.
  • primer extension was analyzed in the presence of either dxGTP or dGTP as controls, and a combination of dxGTP and dGTP at various concentrations.
  • the control reaction in the presence of dxGTP reveals a clearly identifiable pattern of ⁇ inhibition after two dxGMP incorporation events ( Figure 6E, lane 6).
  • the control reaction in the presence of dGTP results in a different pattern.
  • several consecutive dGMPs are incorporated due to multiple misincorporation and mismatch extension events ( Figure 6E, lane 2).
  • ⁇ is among the A-family of polymerases, it includes three insertion motifs which alter the activity of the enzyme relative to other A-family DNA polymerase members.
  • insertion loop 2 which lies between the thumb and palm subdomains confers both translesion synthesis and end-joining activities onto the polymerase (Kent et al., 2015, Nat Struct Mol biol 22:230-7; Hogg et al., 2011, J Mol Biol 405:642-52).
  • ⁇ exhibits a unique ability to incorporate expanded-size dxNMPs, and that the polymerase incorporates dxGMP and dGMP with surprisingly similar steady-state kinetics.
  • B- family replicative polymerases ⁇ and ⁇ exhibit proofreading activity these enzymes can conceivably incorporate a dxNMP then rapidly excise the unnatural nucleotide due to its large base moiety. For example, some evidence was observed for ⁇ dxNMP incorporation; however, dx MP incorporation was not detected by ⁇ . Interestingly, although the respective proofreading functions of ⁇ and ⁇ were activated by the presence of dxNTPs, both enzymes effectively switched to their polymerase activity when equimolar amounts of the respective canonical dNTP were subsequently added to the reaction.
  • ⁇ incorporates dxGMP even when an equimolar amount of dGTP is present in the reaction, which is consistent with its ability to incorporate dGMP and dxGMP with similar kinetics. It is further shown herein that ⁇ becomes arrested after multiple dxGMP incorporation events. This suggests that two closely spaced dxNMPs in the primer induce a severe distortion in the polymerase's active site which suppresses further DNA synthesis either due to preventing proper positioning of the next incoming nucleotide or disabling forward translocation of the polymerase.
  • phosphate prodrug variants of dxG might enable cellular activity against the polymerase which has been shown to promote the survival of HR deficient breast cancer cells (Mateos-Gomez et al., 2015, Nature 518:254-7). Future studies are needed to determine whether ⁇ can be targeted by prodrug size-expanded nucleotide analogs for potential applications in HR deficient cells.
  • Example 2 Use of expanded-size DNA (xDNA) nucleoside and nucleotide analogs to selectively kill recombination-deficient cancer cells
  • nucleoside or nucleotide inhibitors of ⁇ that are specific for this polymerase it is important to first identify nucleotide substrates that are selectively incorporated by ⁇ and not by other polymerases, especially replicative polymerases which are important for the proliferation and survival of non-cancerous cells.
  • xDNA expanded-size DNA
  • dxNMPs deoxynucleoside mono-phosphates
  • dxGTP inhibits ⁇ in vitro and the kinetics of dxGMP and canonical dGMP incorporation by ⁇ are similar, which allows dxGTP to compete with dGTP during ⁇ DNA synthesis.
  • prodrug dxNMPs and prodrug chain teminator versions of dxNMPs can be used to inhibit ⁇ activity in cells and selectively cancer cells that are hyper-dependent on ⁇ such as those deficient in HR.
  • NHEJ non- homologous end-joining
  • dxNMPs are efficiently incorporated by ⁇ , but not by other human polymerases, and that dxGTP inhibits the activity of ⁇ in vitro, prodrug dxNMPs and prodrug chain terminator versions of these dxNMPs will be applicable for inhibiting ⁇ DNA synthesis activity in vivo and selective killing of HR-deficient and potentially NHEJ-deficient cancer cells, while sparing normal cells. Synthetic strategies for deoxygenation of the relevant 3' hydroxyl groups are thus well precedented.
  • prodrug xDNA nucleoside and nucleotide analogs that are applicable for inhibiting ⁇ DNA synthesis activity in cells are illustrated in Figure 7. Some of these nucleotide analogs have been described elsewhere herein. Others represent analogs using similar chemical space that are predicted to inhibit ⁇ based on preliminary research. As illustrated, some nucleotide analogs are utilized as prodrug chain terminators due to either their lack of hydroxyl group at the 3' position of their respective sugar moiety or due to an azide or fluoro group at their respective 3' sugar position. Multiple phosphorus-containing prodrug analogs are contemplated, including known analogs such as "ProTides" derivatives. Generic and specific examples are shown in Figures 8-10.
  • xDNA based nucleoside and nucleotide prodrugs selectively kill HR-deficient cancer cells.
  • the prodrug nucleoside and nucleotide xDNA analogs selectively kill tumors that are deficient in HR as well as other various types of tumors.
  • These prodrug nucleoside and nucleotide xDNA analogs also increase the efficacy of radiation therapy and other forms of cancer therapy involving but not limited to genotoxic agents since ⁇ confers resistance to radiation and various other forms of genotoxic agents and is associated with a poor survival rate for cancer patients.

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Abstract

La présente invention concerne la découverte selon laquelle des nucléotides d'ADN de taille étendue et des analogues de ceux-ci inhibent l'activité de synthèse d'ADN Ροlθ.
PCT/US2017/047508 2016-08-19 2017-08-18 Compositions et procédés de traitement utilisant des analogues d'adn de taille étendue Ceased WO2018035410A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020211668A1 (fr) * 2019-04-15 2020-10-22 Bioardis Llc Inhibiteurs de cd73
WO2021123785A1 (fr) * 2019-12-17 2021-06-24 Artios Pharma Limited Inhibiteurs de l'adn polymérase thêta

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120157404A1 (en) * 2009-05-13 2012-06-21 Gilead Sciences, Inc. Antiviral compounds
WO2015162130A1 (fr) * 2014-04-24 2015-10-29 Eth Zurich Analogues de nucléosides à base modifiée pour la détection de la 06-alkylguanine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120157404A1 (en) * 2009-05-13 2012-06-21 Gilead Sciences, Inc. Antiviral compounds
WO2015162130A1 (fr) * 2014-04-24 2015-10-29 Eth Zurich Analogues de nucléosides à base modifiée pour la détection de la 06-alkylguanine

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020211668A1 (fr) * 2019-04-15 2020-10-22 Bioardis Llc Inhibiteurs de cd73
CN114206841A (zh) * 2019-04-15 2022-03-18 博奥阿迪斯生物科技公司 Cd73抑制剂
WO2021123785A1 (fr) * 2019-12-17 2021-06-24 Artios Pharma Limited Inhibiteurs de l'adn polymérase thêta

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