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WO2012175962A1 - Composés permettant de stabiliser les mutants de p53 - Google Patents

Composés permettant de stabiliser les mutants de p53 Download PDF

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Publication number
WO2012175962A1
WO2012175962A1 PCT/GB2012/051428 GB2012051428W WO2012175962A1 WO 2012175962 A1 WO2012175962 A1 WO 2012175962A1 GB 2012051428 W GB2012051428 W GB 2012051428W WO 2012175962 A1 WO2012175962 A1 WO 2012175962A1
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optionally substituted
independently
compound according
substituents
compound
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Frank Boeckler
Rainer Wilcken
Alan Fersht
Andreas Joerger
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Medical Research Council
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Medical Research Council
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/74—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C215/76—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton of the same non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
    • C07C281/06—Compounds containing any of the groups, e.g. semicarbazides
    • C07C281/08—Compounds containing any of the groups, e.g. semicarbazides the other nitrogen atom being further doubly-bound to a carbon atom, e.g. semicarbazones
    • C07C281/14—Compounds containing any of the groups, e.g. semicarbazides the other nitrogen atom being further doubly-bound to a carbon atom, e.g. semicarbazones the carbon atom being further bound to a carbon atom of a six-membered aromatic ring
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/48—Oxygen atoms attached in position 4 having an acyclic carbon atom attached in position 4
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds that have the ability to bind to p53 protein molecules, the use of such compounds and the compounds per se.
  • tumour suppressor protein p53 is a 393 amino acid transcription factor that regulates the cell cycle and plays a key role in the prevention of cancer development, thus sometimes dubbed the 'guardian of the genome' (1 ).
  • p53 can initiate the transcription of a multitude of genes resulting in a variety of cellular outcomes.
  • tumour suppression pathways have been described for p53 depending on the tissue, the cell context, as well as the character, duration, and intensity of the stress signal (2).
  • apoptosis genes such as Bax, Noxa and PUMA (3, 4), and genes such as p21 and others connected with G1 and G2 cell cycle arrest and DNA repair (2, 5, 6).
  • apoptosis genes such as Bax, Noxa and PUMA (3, 4)
  • genes such as p21 and others connected with G1 and G2 cell cycle arrest and DNA repair (2, 5, 6).
  • p53 is often directly inactivated by mutation (8).
  • Somatic TP53 mutations occur in almost every type of cancer at rates from 38%-50% in ovarian, esophageal, colorectal, head and neck, larynx, and lung cancers to about 5% in primary leukemia, sarcoma, testicular cancer, malignant melanoma, and cervical cancer (9).
  • the multi-functionality of p53 is reflected in the complexity of its structure.
  • Each chain in the p53 tetramer is composed of several domains. There are well-defined DNA-binding and tetramerization domains and highly mobile, largely unstructured regions (10-15).
  • Most p53 cancer mutations are located in the DNA-binding core domain of the protein (8, 9). This domain has been structurally characterized in complex with its cognate DNA by X-ray crystallography (10) and in its free form in solution by NMR (1 6). It consists of a central ⁇ -sandwich of two anti-parallel ⁇ - sheets that serves as basic scaffold for the DNA-binding surface.
  • the DNA- binding surface is composed of two ⁇ -turn loops (L2 and L3) that are stabilized by a zinc ion and a loop-sheet-helix motif. Together, these structural elements form an extended DNA-binding surface that is rich in positively charged amino acids and makes specific contacts with the various p53 response elements.
  • thermodynamically destabilize the folded protein (1 7). While structural changes in the DNA-binding region result in loss of DNA-binding affinity, destabilization of the core domain leads to rapid thermal denaturation of p53 at body temperature because wild-type p53 already is an intrinsically unstable protein (18, 19).
  • a functional thermostable synthetic variant of p53 referred to as " 7 " -p53C” has been used (20). This variant has the substitutions M133L, V203A, N239Y and N268D.
  • This construct which otherwise has essentially wild-type characteristics, has been used as a vector to carry various known oncogenic mutations of p53 in a form that allows determination of their structure by X-ray crystallography.
  • Y220C is the most common mutation outside the DNA-binding surface, with about 75,000 new cancer cases being reported per year (21 ). It is located at the far end of the ⁇ -sandwich at the start of the turn connecting ⁇ -strands S7 and S8.
  • the structure of 7 " -p53C with the Y220C mutation has been described (22). With tyrosine at position 220, the benzene moiety of Tyr-220 forms part of the hydrophobic core of the beta-sandwich, whereas the hydroxyl group points toward the solvent.
  • the mutation creates a solvent-accessible cleft that is filled with water molecules at defined positions but leaves the overall structure of the core domain intact.
  • Boeckler et al. (21 ) were able to identify the small molecule binder PhiKan083 which reversibly binds to the mutation-induced cavity of the 7 " -p53C-Y220C mutant with reasonable affinity ( d ⁇ 150 ⁇ ) and stabilizes the mutant by increasing its melting temperature.
  • This approach represents the first successful attempt to develop a lead that specifically reactivates a p53 mutant.
  • We have developed a novel class of compounds that exhibit improved binding properties show improved stabilization of the Y220C mutant protein, substantially delay its aggregation and are able to stabilize p53-Y220C in vivo in a cancer cell line (H1 299).
  • the present inventors have discovered that a number of compounds which contain a benzene or pyridine core, or a related scaffold, bind to 7 " -p53C-Y220C and stabilizes the protein so as to alter, such as to increase, its melting temperature.
  • a compound of formula (I) as described herein for use in a method of treatment of a subject who has a lesion or a tumour in which p53 carries a Y220C mutation.
  • the invention provides a method for treating a cell in which p53 carries a Y220C mutation, the method comprising contacting the cell with a compound of formula (I).
  • the invention provides a method for treating a subject who has a lesion or a tumour in which p53 carries a Y220C mutation, the method comprising administering to the subject a compound of formula (I).
  • the invention provides a compound of formula (I) for use in a method of treatment of a subject who has a lesion or a tumour in which p53 carries a Y220C mutation.
  • the invention further provides a method of determining the binding of a molecule to a p53 which carries a Y220C mutation, the method comprising bringing the molecule into contact with said p53 in competition with a compound of formula (I), and measuring the binding or displacement of one or other of said compounds.
  • one or both of the compounds may carry a label, such as a radiolabel, chromophore, fluorophore or a fluorine function for competition- based 9 F-screening using magnetic resonance techniques.
  • a further aspect of the present invention relates to novel compounds within formula (I), for example compounds of formula (IV).
  • Figure 1 shows the effect of PK5174 on 7 " -p53C-Y220C aggregation
  • Figure 2 shows the effect of PK5176 on 7 " -p53C-Y220C aggregation.
  • Figure 3 shows the K D for PK5176 from nucleation (ki) part of aggregation (modified Finke-Watzky model).
  • Figure 4 shows that k 2 (growth) rates do not change significantly upon increasing compound concentration.
  • Figure 5 shows the initial rates of scattering in the presence of PK5174.
  • Figure 6 shows the initial rates of scattering in the presence of PK5176.
  • Figure 7 shows the K D from initial rates of scattering for PK51 74.
  • Figure 8 shows the K D from initial rates of scattering for PK51 76.
  • Figures 9 A-K are the crystal structures of T-p53C-Y220C ligand complexes with (A) PK5086, (B) PK5174, (C) PK5176, (D) PK51 16, (E) PK51 17, (F) PK51 18, (G) PK51 85, (H) PK5188, (I) PK51 91 , (J) PK5090.
  • K is the superposition of PK5090 and PK5176 binding modes.
  • Figure 10 is a series of Western Blots demonstrating the effect of p53-Y220C stabilization by PK5174.
  • Figure 1 1 is a series of graphs showing the effects of PK51 1 6 (a), PK5174 (b) and PK51 96 (c) in NUGC-3 (p53-Y220C +/+ ) and NUGC-4 (p53-wt +/+ ) cell lines at different concentrations. While PK51 16 does not induce Caspase-3/7 activation, apoptosis is induced by the more potent binders PK5174 and PK5196 at high concentrations in Y220C mutant cells, but not in wild-type cells.
  • Figure 1 2 is a series of images of gels showing p53 and p21 protein levels in human cancer cells after 5h treatment with PK5201 .
  • p21 levels are elevated with increasing compound concentrations in NUGC-3 (p53-Y220C +/+ ) cells.
  • the p21 levels are constantly low in MKN-1 3 (p53-V1 43A +/+ ) and constantly high in NUGC-4 (p53-wt +/+ ) cell lines and are not influenced by PK5201 .
  • Figure 1 3 is confocal microscopy images of_NUGC-3 (p53-Y220C +/+ ) cells with and without treatment with PK5201 .
  • the DAPI stain is in blue. Folded p53 levels increase markedly after treatment of NUGC-3 cells with PK5201 for 4 hours (bottom row).
  • Figure 14 is a series of graphs showing the effect of (a) PhiKan51 16, (b)
  • a compound for use in a method of treatment of a subject who has a lesion or a tumour in which p53 carries a Y220C mutation in which the compound is selected from compounds of the following formula (I), and pharmaceutically acceptable salts, hydrates, a
  • A is independently CR 4 or N ;
  • -Ri is independently selected from -OH , -OMe, -NH 2 , -SH, -F and -CF 3 ;
  • -Pt 2 is independently selected from -I , -CI, -Br, and ethynyl (-C ⁇ CH) ;
  • -R 3 is independently selected from -R 3S , -I , -Br, -CI, ethynyl (-C ⁇ CH), -H , -OMe, and -N0 2 ; wherein -R 3S is independently selected from :
  • -R 6 A is independently saturated aliphatic d ioalkyl and is optionally substituted with one or more substituents -R T ,
  • -R 6 B is independently saturated C 3 -ioCycloalkyl and is optionally substituted with one or more substituents -R T ,
  • -R 6 c is independently -Qi or -Q 2 ,
  • -Qi is independently C 6 -i 0 carboaryl, and is optionally substituted with one or more substituents -R T ,
  • -Q 2 is independently C 5 .i 2 heteroaryl, and is optionally substituted with one or more substituents -R T ,
  • -R 6D is independently aliphatic C 2 - 7 alkenyl and is optionally substituted with one or more substituents -R T ,
  • -R 6E is independently aliphatic C 2 . 6 alkynyl and is optionally substituted with one or more substituents -R T ,
  • -R 6F is independently C 3 . 6 cycloalkenyl and is optionally substituted with one or more substituents -R T ,
  • -R 6G is independently C 3- i 0 heterocyclyl, where the carbon ring atoms are optionally substituted with one or more substituents - R T , and any nitrogen ring atoms, where present, are optionally substituted with -R TN , and the heterocyclyl optionally comprises one or more double bonds,
  • each -R T is independently selected from:
  • each -RTN is independently selected from:
  • each -R E is independently -R E i, -RE 2 , -RE3, -RE 4 , -RES, -RE6 or -R E7 ;
  • each -R E1 is independently saturated aliphatic Ci_i 0 alkyl and is optionally substituted with one or more substituents -R S ;
  • each -R E2 is independently saturated C 3 -i 0 cycloalkyl and is optionally substituted with one or more substituents -R S ; each -R E
  • -R 4 is independently selected from -H and -R 4 s; where -R 4S is independently selected from:
  • each -R w is independently -Rwi , -Rw2, -Rw3, -Rw4, - Rw5, -Rwe or -R W 7; each -Rwi is independently saturated aliphatic Ci-i 0 alkyl and is optionally substituted with one or more substituents -R s ; each -R W 2 is independently saturated C 3 -i 0 cycloalkyl and is optionally substituted with one or more substituents -R s ; each -R W3 is independently -Qi or -Q 2 ; -Qi is independently C 6- i 0 carboaryl, and is optionally substituted with one or more substituents -R s ;
  • each -Rw 7 is independently C 3 -ioheterocyclyl where the carbon ring atoms are optionally substituted with one or more substituents -R s , and any nitrogen ring atoms, where present, are optionally substituted with -R S N, and the heterocyclyl optionally comprises one or more double bonds, each -NR WN1 R WN2 , if present, is independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, azepano, diazepano, thiomorpholino, oxidised thiomorpholino, or octahydro-pyrrolo[1 ,2-a]pyrazino, where the carbon ring atoms are optionally substituted with one or more substituents -R s , and any nitrogen ring atoms, where present,
  • -R 5 is independently selected from -COOH and: formula Ilia formula 1Mb formula 111
  • -R 7A is independently -H or -R s ;
  • -R 7B is independently -H or -R s ;
  • -R 8 is independently selected from:
  • Ri 3 is independently selected from -H and -R S N ; and -L N - is independently selected from: where -L N i - is saturated d- 6 alkylene, and is optionally substituted by one or more substituents -R s ;
  • -Rci and -R C2 together with the carbon atom to which they are attached form a C 3 -i 0 cyclohexyl ring where the carbon ring atoms are optionally substituted with one or more substituents -R N , and any nitrogen ring atoms, where present, are optionally substituted with -R NN , and the heterocyclyl optionally comprises one or more double bonds;
  • -R N i is independently selected from -NH 2 , -NHR E , -N(R E ) 2 , and -R EN1 where -R E NI is a C 3 .i 0 cyclohexyl ring where the carbon ring atoms are optionally substituted with one or more substituents - R N , and any nitrogen ring atoms, where present, are optionally substituted with -R NN , and the heterocyclyl optionally comprises one or more double bonds
  • -R N4 is independentlysaturated aliphatic d- 6 alkyl and is optionally substituted with one or more substituents -R S ;
  • -R N 5 is independently a nitrogen-containing C 3 -ioheterocyclyl group, and the carbon ring atoms are optionally substituted with one or more substituents -R N , and any nitrogen ring atoms, where present, are optionally substituted with
  • each -R N is independently selected from:
  • each -R NN is independently selected from:
  • each -R S is independently selected from:
  • each - R S N is independently selected from:
  • each -R B is independently -R S i , -R S2 > -Rsa. - Rs4 > -Rss.
  • each -Rsi is independently saturated aliphatic Ci_i 0 alkyl and is optionally substituted with one or more substituents selected from: -F, -CI, -Br, -I, -CF 3 , -OH, -OR W11 , and -OCF 3 , wherein each -R W 1 is independently saturated aliphatic Ci- 4 alkyl; each -R S2 is independently saturated C 3 - 6 cycloalkyl and is optionally substituted with one or more substituents selected from: -R W n , -F, -CI, -Br, -I, -CF 3 , -OH, -CN, and -N0 2 , -OR W n , and -OCF 3 , wherein each -R W n is
  • each -R S3 is independently -Q 3 or -Q 4 ;
  • -Q 3 is independently C 6 -iocarboaryl, and is optionally substituted with one or more substituents selected from: -R W n , -F, -CI, -Br, -I, -CF 3 , -OH, -CN, and -N0 2 , -ORwii , and -OCF 3 , wherein each -R W n is independently saturated aliphatic Ci- 4 alkyl;
  • -Q 4 is independently C 5 -i 2 heteroaryl, and is optionally substituted with one or more substituents selected from: -R W n , -F, -CI, -Br, -I, -CF 3 , -OH, -CN, and -N0 2 , -ORwii , and -OCF 3 , wherein each -R
  • each -R S5 is independently aliphatic C 2 . 6 alkynyl and is optionally
  • each -R S6 is independently C 3 - 6 cycloalkenyl and is optionally substituted with one or more substituents selected from: -R W n , -F, -CI, -Br, -I, -CF 3 , -OH, -CN, and -N0 2 , -OR W n , and -OCF 3 , wherein each -R W n is independently saturated aliphatic C 1-4 alkyl; each -R S7 is independently C 3 _i 0 heterocyclyl where the carbon ring atoms are optionally substituted with one or more substituents selected from: -R W n , -F, -CI, -Br, -I, -CF 3 , -OH, -CN, and -N0 2 , -0R W11 , and -OCF 3 , wherein each -R W11 is independently saturated alipha
  • each -R 6A if present, is independently saturated aliphatic d- 6 alkyl and is optionally substituted with one or more substituents -R T .
  • each -R 6A if present, is independently saturated aliphatic d- 4 alkyl and is optionally substituted with one or more substituents -R T .
  • each -R 6A is independently -Me, -Et, -nPr, -iPr, or -tBu, and is optionally substituted with one or more substituents -R T .
  • each -R 6A if present, is independently -Me or -Et, and is optionally substituted with one or more substituents -R T .
  • each -R 6A if present, is independently -Me, and is optionally substituted with one or more substituents -R T .
  • the Group -R 6B (46) A compound according to any one of (1 ) to (45), wherein -R 6B , if present, is saturated C 3 -i 0 cycloalkyl and is substituted with -R T at the carbon atom geminal to the point of attachment, and optionally one or more further substituents -R T . (47) A compound according to any one of (1 ) to (45), wherein -R 6B , if present, is saturated C 3 - 6 cycloalkyl and is substituted with -R T at the carbon atom geminal to the point of attachment, and optionally one or more further substituents -R T .
  • the group shown below is illustrative of a C 3 - 6 cycloalkyl having a substituent -R T . at the carbon atom geminal to the point of attachment, (as indicated by the wavy line) and optionally one or more further substituents -R T .
  • each -R 6D is independently aliphatic C 2 - 4 alkenyl, and is optionally substituted with one or more substituents -R T .
  • each -R 6E if present, is independently -C ⁇ CH, -C ⁇ C-CH 3 , or -C ⁇ C-CH 2 -CH 3 , and is optionally substituted with one or more substituents -R T .
  • each -R 6F is independently cyclopentenyl or cyclohexenyl, and is optionally substituted with one or more substituents -R T .
  • each -R 6G if present, is C 3 . 7 heterocyclyl and the carbon ring atoms are optionally substituted with one or more substituents -R T , and any nitrogen ring atoms, where present, are optionally substituted with -R TN , and the heterocyclyl optionally comprises one or more double bonds.
  • each -R 6G if present, is C 3 - 7 heterocyclyl and the carbon ring atoms are optionally substituted with one or more substituents -R T , and any nitrogen ring atoms, where present, are optionally substituted with -R T N- (64)
  • each -R 6G is independently selected from pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, and oxidised thiomorpholino, and the carbon ring atoms are optionally substituted with one or more substituents -R T , and any nitrogen ring atoms, where present, are optionally substituted with -R T N- (66)
  • the Group -R T (79) A compound according to any one of (1 ) to (78), wherein each -R T , if present, is independently selected from: -F, -CI, -Br, -I,
  • -Q 2 if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, or isothiazolyl, and is optionally substituted with one or more substituents -R s
  • -Q 2 if present, is independently furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, or isothiazo
  • the Group -R 7B (128) A compound according to any one of (1 ) to (127), wherein -R 7B , if present, is -H.
  • (140) A compound according to any one of (1 ) to (139), wherein -L N i - , if present, is saturated aliphatic d. 6 alkylene and is optionally substituted with one or more substituents -R S .
  • (141 ) A compound according to any one of (1 ) to (139), wherein -L N1 -, if present, is linear saturated d- 6 alkylene and is optionally substituted with one -R S .
  • the Group -R N1 (157) A compound according to any one of (1 ) to (156), wherein -R N1 , if present, is -N(R E ) 2 or -R EN1 .
  • carbon ring atoms are optionally substituted with one or more substituents -R N , and any nitrogen ring atoms, where present, are optionally substituted with -R N N .
  • carbon ring atoms are optionally substituted with one or more substituents -R N , and any nitrogen ring atoms, where present, are optionally substituted with -R NN .
  • carbon ring atoms are optionally substituted with one or more substituents -R N , and any nitrogen ring atoms, where present, are optionally substituted with -R NN .
  • carbon ring atoms are optionally substituted with one or more substituents -R N , and any nitrogen ring atoms, where present, are optionally substituted with -R NN .
  • carbon ring atoms are optionally substituted with one or more substituents -R N , and any nitrogen ring atoms, where present, are optionally substituted with -R NN .
  • carbon ring atoms are optionally substituted with one or more substituents -R N , and any nitrogen ring atoms, where present, are optionally substituted with -R NN .
  • (183) A compound according to any one of (1 ) to (173), wherein -NR N2 R N3 , if present, is independently diazepano, and the carbon ring atoms are optionally substituted with one or more substituents -R N , and any nitrogen ring atoms, where present, are optionally substituted with -R NN .
  • carbon ring atoms are optionally substituted with one or more substituents -R N , and any nitrogen ring atoms, where present, are optionally substituted with -R NN .
  • carbon ring atoms are optionally substituted with one or more substituents -R N , and any nitrogen ring atoms, where present, are optionally substituted with -R NN .
  • carbon ring atoms are optionally substituted with one or more substituents -R N , and any nitrogen ring atoms, where present, are optionally substituted with -R NN .
  • the Group -R NN (199) A compound according to any one of (1 ) to (198), wherein -R NN , if present, is independently selected from:
  • the Group -R N4 (203) A compound according to any one of (1 ) to (202), wherein -R N4 , if present, is saturated aliphatic d- 3 alkyl and is optionally substituted with one or more substituents -R S .
  • carbon ring atoms are optionally substituted with one or more substituents -R T , and any nitrogen ring atoms, where present, are optionally substituted with -R T N-
  • carbon ring atoms are optionally substituted with one or more substituents -R T , and any nitrogen ring atoms, where present, are optionally substituted with -R T N-
  • carbon ring atoms are optionally substituted with one or more substituents -R T , and any nitrogen ring atoms, where present, are optionally substituted with -R T N-
  • each -R W is independently -R W i , -Rw2, -Rw3, or -R W 7- (210)
  • each -R W is independently -Me, -Et, -nPr, -iPr, or -tBu, and is optionally substituted with one or more substituents -R S .
  • each -R W 2 is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and is optionally substituted with one or more substituents -R s .
  • each -R W 4 if present, is independently aliphatic C 2 - 4 alkenyl, and is optionally substituted with one or more substituents -R s .
  • each -R W 5, if present, is independently -C ⁇ CH, -C ⁇ C-CH 3 , or -C ⁇ C-CH 2 -CH 3 , and is optionally substituted with one or more substituents -R s .
  • each -R W6 is independently cyclopentenyl or cyclohexenyl, and is optionally substituted with one or more substituents -R S .
  • the Group -R W7 (232) A compound according to any one of (1 ) to (231 ), wherein each -R W7 , if present, is C 3 - 7 heterocyclyl and the carbon ring atoms are optionally substituted with one or more substituents -R T , and any nitrogen ring atoms, where present, are optionally substituted with -R T N, and the heterocyclyl optionally comprises one or more double bonds.
  • each -R W7 is independently selected from azetidino, pyrrolidino, piperidino, piperazino, morpholino, azepano, diazepano, thiomorpholino, oxidised
  • -NRWNI RWN2 if present, is independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, azepano, diazepano, thiomorpholino, oxidised
  • R WN R WN2 is independently pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or oxidised thiomorpholine, , where the carbon ring atoms are optionally substituted with one or more substituents -R S , and any nitrogen ring atoms, where present, are optionally substituted with -R SN -
  • each -R E i is independently saturated aliphatic Ci_ 6 alkyl and is optionally substituted with one or more substituents -R s
  • each -R E i is independently -Me, -Et, -nPr, -iPr, or -tBu , and is optionally substituted with one or more substituents -R s .
  • each -R E1 if present, is independently -Me or -Et, and is optionally substituted with one or more substituents -R s .
  • each -R E2 is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and is optionally substituted with one or more substituents -R s .
  • each -R E2 if present, is independently cyclopropyl, and is optionally substituted with one or more substituents -R s .
  • the Group -R E3 (251 ) A compound according to any one of (1 ) to (250), wherein each -R E3 , if present, is -Qi .
  • each -R E4 if present, is independently aliphatic C 2 - 4 alkenyl, and is optionally substituted with one or more substituents -R s .
  • the Group -R E5 (256) A compound according to any one of (1 ) to (255), wherein each -R E5 , if present, is independently -C ⁇ CH, -C ⁇ C-CH 3 , or -C ⁇ C-CH 2 -CH 3 , and is optionally substituted with one or more substituents -R s .
  • each -R E5 if present, is independently -C ⁇ CH, and is optionally substituted with one or more substituents -R s .
  • each -R E6 is independently cyclopentenyl or cyclohexenyl, and is optionally substituted with one or more substituents -R s .
  • each -R E7 if present, is C 3 . 7 heterocyclyl and the carbon ring atoms are optionally substituted with one or more substituents -R T , and any nitrogen ring atoms, where present, are optionally substituted with -R TN .
  • each -R E7 is independently selected from azetidino, pyrrolidino, piperidino, piperazino, morpholino, azepano, diazepano, thiomorpholino, oxidised
  • each -R E7 is independently selected from pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, and oxidised thiomorpholino, and the carbon ring atoms are optionally substituted with one or more substituents -R T , and any nitrogen ring atoms, where present, are optionally substituted with -R T N-
  • each -R E is independently selected from azetidino, pyrrolidino, piperidino, and piperazino, and the carbon ring atoms are optionally substituted with one or more substituents -R T , and any nitrogen ring atoms, where present, are optionally substituted with -R T N-
  • each -NR EN i R EN2 is independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, azepano, diazepano, thiomorpholino, oxidised thiomorpholino, or octahydro-pyrrolo[1 ,2-a]pyrazino, where the carbon ring atoms are optionally substituted with one or more substituents -R s , and any nitrogen ring atoms, where present, are optionally substituted with -R S N-
  • each -NR EN R EN2 is independently pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or oxidised thiomorpholine, where the carbon ring atoms are optionally substituted with one or more substituents -R S , and any nitrogen ring atoms, where present, are optionally substituted with -R S N-
  • each -R s is independently -R S i , -Rs2, -F1 ⁇ 2 or -R S7 .
  • each -R S i is independently saturated aliphatic d- 6 alkyl and is optionally substituted with one or more substituents selected from: -F, -CI, -Br, -I, -CF 3 , -OH, -OR W11 , and -OCF 3 , wherein each -R W 1 is independently saturated aliphatic Ci- 4 alkyl
  • each -R S i is independently saturated aliphatic Ci_ 4 alkyl and is optionally substituted with one or more substituents selected from: -F, -CI, -Br, -I, -CF 3 , -OH, -OR W11 , and -OCF 3 , wherein each -R W 1 is independently saturated aliphatic Ci- 4 alkyl
  • each -R S i is independently -Me, -Et, -nPr, -iPr, or -tBu, and is optionally substituted with one or more substituents selected from: -F, -CI, -Br, -I, -CF 3 , -OH, -OR W11 , and -OCF 3 , wherein each -R W 1 is independently saturated aliphatic Ci_ 4 alkyl.
  • each -R S i is independently -Me or -Et, and is optionally substituted with one or more substituents selected from: -F, -CI, -Br, -I, -CF 3 , -OH, -OR W11 , and -OCF 3 , wherein each -R W 1 is independently saturated aliphatic C 1 _ 4 alkyl.
  • each -R S i is independently -Me, and is optionally substituted with one or more substituents selected from: -F, -CI, -Br, -I, -CF 3 , -OH, -OR W11 , and -OCF 3 , wherein each -R W 1 is independently saturated aliphatic C 1 _ 4 alkyl.
  • each -R S2 is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and is optionally substituted with one or more substituents selected from: -R W n , -F, -CI, -Br, -I, -CF 3 , -OH, -CN, and -N0 2 , -OR W n , and -OCF 3 , wherein each -R W n is independently saturated aliphatic Ci_ 4 alkyl.
  • each -R E2 if present, is independently cyclopropyl, and is optionally substituted with one or more substituents selected from: -R W n , -F, -CI, -Br, -I, -CF 3 , -OH, -CN, and -N0 2 , -ORwii , and -OCF 3 , wherein each -R W11 is independently saturated aliphatic Ci- 4 alkyl.
  • the Group -R S3 (285) A compound according to any one of (1 ) to (284), wherein each -R S3 , if present, is -Qi .
  • (290) A compound according to any one of (1 ) to (289), wherein -Q 2 , if present, is independently C 5 . 6 heteroaryl or C 9 .i 0 heteroaryl, and is optionally substituted with one or more substituents selected from: -R W n , -F, -CI, -Br, -I, -CF 3 , -OH, -CN, and -N0 2 , -ORwii , and -OCF 3 , wherein each -R W n is independently saturated aliphatic Ci -4 alkyl.
  • benzothiazolyl benzoisoxazolyl, benzoisothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, quinazolinyl, or phthalazinyl, and is optionally substituted with one or more substituents selected from: -R W n , -F, -CI, -Br, -I, -CF 3 , -OH, -CN, and -N0 2 , -OR W n , and -OCF 3 , wherein each -R W n is independently saturated aliphatic C 1 _ 4 alkyl.
  • the Group -R S 4 (298) A compound according to any one of (1 ) to (297), wherein each -R S4 , if present, is independently aliphatic C 2 . 4 alkenyl, and is optionally substituted with one or more substituents selected from: -R W n , -F, -CI, -Br, -I, -CF 3 , -OH, -CN, and -NO2, -ORwii , and -OCF 3 , wherein each -R W n is independently saturated aliphatic Ci- 4 alkyl.
  • the Group -R S 5 is independently saturated aliphatic Ci- 4 alkyl.
  • each -R S5 if present, is independently -C ⁇ CH, -C ⁇ C-CH 3 , or -C ⁇ C-CH 2 -CH 3 , and is optionally substituted with one or more substituents selected from: -R W n , -F, -CI, -Br, -I, -CF 3 , -OH, -CN, and -N0 2 , -OR W n , and -OCF 3 , wherein each -R W11 is independently saturated aliphatic C -4 alkyl.
  • each -R S5 if present, is independently -C ⁇ CH, and is optionally substituted with one or more substituents selected from: -R W n , -F, -CI, -Br, -I, -CF 3 , -OH, -CN, and -N0 2 , -ORwii , and -OCF 3 , wherein each -R W11 is independently saturated aliphatic Ci- 4 alkyl.
  • the Group -R S e (303) A compound according to any one of (1 ) to (302), wherein each -R S6 , if present, is independently cyclopentenyl or cyclohexenyl, and is optionally substituted with one or more substituents selected from: -R W n , -F, -CI, -Br, -I, -CF 3 , -OH, -CN, and -N0 2 , -OR W n , and -OCF 3 , wherein each -R W n is
  • each -R E6 if present, is independently: and is optionally substituted with one or more substituents selected from: -R W n , -F, -CI, -Br, -I, -CF 3 , -OH, -CN, and -N0 2 , -OR W n , and -OCF 3 , wherein each -R W1 1 is independently saturated aliphatic C 1 -4 alkyl.
  • each -N R SN i RSN 2 is independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, azepano, diazepano, thiomorpholino, oxidised thiomorpholino, or octahydro-pyrrolo[1 ,2-a]pyrazino, where the carbon ring atoms are optionally substituted with one or more substituents selected from: -R W n , -F, -CI , -Br, - I , -CF 3 , -OH , -CN , and -N0 2 , -OR W n , and -OCF 3 , wherein each -R W n is
  • each -N R EN R EN2 is independently pyrrolidino, piperidino, piperazino, morpholino, thiomorpholino, or oxidised thiomorpholine, where the carbon ring atoms are optionally substituted with one or more substituents selected from: -R W n , -F, -CI , -Br, - I , -CF 3 , -OH , -CN , and -N0 2 , -OR W n , and -OCF 3 , wherein each -R W n is independently saturated aliphatic d- 4 alkyl; and any nitrogen ring atoms, where present, are optionally substituted with - R W n or -CF 3 .
  • -Ri , -R 2 , -R 6 , -R 7A , -R 7B , and -R 8 are as defined in any one of (1 ) to
  • -Ri , -R 2 , -Re, and -R 8 are as defined in any one of (1 ) to (307), where present..
  • -Ri , -R 2 , and -R 3 are as defined in any one of (1 ) to (307), where present, and the carbon ring atoms of the piperazine are optionally substituted with one or more substituents -R N , and a further nitrogen ring atom, where present, is optionally substituted with -R NN .
  • -Ri , -R 2 , and -R 3 are as defined in any one of (1 ) to (307), where present, and the carbon ring atoms of the piperazine are optionally substituted with one or more substituents -R N , and a further nitrogen ring atom, where present, is optionally substituted with -R NN .
  • -Ri , -R 2 , and -R 3 are as defined in any one of (1 ) to (307), where present, and the carbon ring atoms of the piperazine are optionally substituted with one or more substituents -R N .
  • C 3 -i 0 heterocyclyl may encompass fused ring systems.
  • a reference to a carboaryl, heteroaryl, cycloalkyi, heterocyclyl, or cycloalkenyl group as being substituted with a carboaryl, heteroaryl, cycloalkyi, heterocyclyl, or cycloalkenyl group may be construed as referred to the fusion of the first ring system with the second ring system.
  • the present invention relates to a p53 protein carrying a 220C mutation.
  • a p53 protein which carries a Y220C mutation may be the wild-type mammalian, particularly human, protein, or a stabilized version thereof.
  • SEQ ID NO:1 (AAC12971 ) provides the wild-type human sequence of p53. The use of human p53 is preferred.
  • the p53 protein may be a truncated p53 comprising the DNA-binding domain.
  • a domain will generally comprise the region corresponding to residues 95 to 289 of the human sequence. Examples of such domains are found in Joerger et a/ (Ref. 22), e.g. the region corresponding to residues 94-312 of the human sequence or a truncation thereof, such as 94-293.
  • the invention may use full length or truncated p53 proteins as described above, and may incorporate one or more stabilizing alteration, e.g. one or more of the substitutions found in 7 ⁇ -p53C.
  • the p53 will be native to the cell in which it is present.
  • a p53 native to the cell in which it is present will correspond to the wild type sequence of p53 apart from the substitution at the position equivalent to residue 220 of SEQ ID NO:1 .
  • the protein may comprise one or more other mutations.
  • the present invention provides a compound of formula (I) as defined in any one of (1 ) to (325).
  • the compounds of the present invention are for use in the stabilisation of a p53 mutant. Stabilisation of the mutant may be determined experimentally by measurement of the change in melting point temperature of the p53 mutant. In one embodiment, of the invention the compounds of the invention increase the melting point temperature of the p53 mutant. Changes in melting point temperature may be determined from
  • DSF differential scanning fluorimetry
  • the increase in melting point temperature (i.e. positive ⁇ T m ) is at least 0.01 , at least 0.05, at least 0.1 0, at least 0.20, at least 0.30, at least 0.40, at least 0.50, at least 0.60 °C.
  • the compounds of the present invention are suitable for binging to a p53 mutant.
  • the binding affinity expressed as the dissociation constant K d , is at least 5, at least 10, at least 50, at least 100, at least 200, at least 500, at least 1000, at least 2,000, or at least 5,000 ⁇ .
  • K d may refer to the dissociation constant at 20 °C.
  • K d is determined by isothermal titration calorimetry (ITC) or by H/ 5 N -HSQC NMR spectroscopy. Such methods may be conducted as described herein.
  • the substantially purified form is at least 50% by weight, e.g., at least 60% by weight, e.g., at least 70% by weight, e.g., at least 80% by weight, e.g., at least 90% by weight, e.g., at least 95% by weight, e.g., at least 97% by weight, e.g., at least 98% by weight, e.g., at least 99% by weight.
  • the substantially purified form refers to the compound in any stereoisomeric or enantiomeric form.
  • the substantially purified form refers to a mixture of stereoisomers, i.e., purified with respect to other compounds.
  • the substantially purified form refers to one stereoisomer, e.g., optically pure stereoisomer.
  • the substantially purified form refers to a mixture of enantiomers.
  • the substantially purified form refers to an equimolar mixture of enantiomers (i.e., a racemic mixture, a racemate).
  • the substantially purified form refers to one enantiomer, e.g., optically pure
  • the contaminants represent no more than 50% by weight, e.g., no more than 40% by weight, e.g., no more than 30% by weight, e.g., no more than 20% by weight, e.g., no more than 1 0% by weight, e.g., no more than 5% by weight, e.g., no more than 3% by weight, e.g., no more than 2% by weight, e.g., no more than 1 % by weight.
  • the contaminants refer to other compounds, that is, other than stereoisomers or enantiomers. In one embodiment, the contaminants refer to other compounds and other stereoisomers. In one embodiment, the contaminants refer to other compounds and the other enantiomer.
  • the substantially purified form is at least 60% optically pure (i.e., 60% of the compound, on a molar basis, is the desired stereoisomer or enantiomer, and 40% is the undesired stereoisomer or enantiomer), e.g., at least 70% optically pure, e.g., at least 80% optically pure, e.g., at least 90% optically pure, e.g., at least 95% optically pure, e.g., at least 97% optically pure, e.g., at least 98% optically pure, e.g., at least 99% optically pure.
  • 60% optically pure i.e., 60% of the compound, on a molar basis, is the desired stereoisomer or enantiomer, and 40% is the undesired stereoisomer or enantiomer
  • at least 70% optically pure e.g., at least 80% optically pure, e.g., at least 90% optically pure, e
  • Certain compounds, as defined in any one of (1 ) to (325), may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; a- and ⁇ -forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or "iso
  • isomers are structural (or constitutional) isomers (i.e., isomers which differ in the connections between atoms rather than merely by the position of atoms in space).
  • a reference to a methoxy group, -OCH 3 is not to be construed as a reference to its structural isomer, a
  • ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl.
  • a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., d- 7 alkyl includes n-propyl and iso- propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).
  • d- 7 alkyl includes n-propyl and iso- propyl
  • butyl includes n-, iso-, sec-, and tert-butyl
  • methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl
  • keto/enol illustrated below
  • imine/enamine amide/imino alcohol
  • H may be in any isotopic form, including H, 2 H (D), and 3 H (T); C may be in any isotopic form, including 2 C, 3 C, and 4 C; O may be in any isotopic form, including 6 0 and 8 0; and the like.
  • a reference to a particular compound includes all such isomeric forms, including mixtures (e.g., racemic mixtures) thereof.
  • Methods for the preparation e.g., asymmetric synthesis
  • separation e.g., fractional crystallisation and chromatographic means
  • isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner.
  • a salt may be formed with a suitable cation.
  • suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K + , alkaline earth cations such as Ca 2+ and Mg 2+ , and other cations such as ⁇ 3 .
  • Suitable organic cations include, but are not limited to, ammonium ion (i.e., NH 4 + ) and substituted ammonium ions (e.g., NH 3 R + , ⁇ 2 ⁇ 2 + , NHR 3 + , NR 4 + ).
  • suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperizine, benzylamine, phenylbenzylamine, choline,
  • a salt may be formed with a suitable anion.
  • suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.
  • Suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic,
  • ethanesulfonic fumaric, glucheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, and valeric.
  • suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.
  • a reference to a particular compound also includes salt forms thereof.
  • solvate is used herein in the conventional sense to refer to a complex of solute (e.g., compound, salt of compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono- hydrate, a di-hydrate, a tri-hydrate, etc.
  • a reference to a particular compound, as defined in any one of (1 ) to (325), also includes solvate and hydrate forms thereof.
  • composition e.g., a composition
  • a composition e.g., a composition
  • composition comprising a compound, as defined in any one of (1 ) to (325), and a pharmaceutically acceptable carrier, diluent, or excipient.
  • the composition optionally comprises a second active agent.
  • Another aspect of the present invention pertains to a method of preparing a composition (e.g., a pharmaceutical composition) comprising admixing an compound, as defined in any one of (1 ) to (325), and a pharmaceutically acceptable carrier, diluent, or excipient.
  • Another aspect of the present invention pertains to a compound, as defined in any one of (1 ) to (325), for use in a method of altering the stability of a p53 mutant.
  • the alteration may be a change in the melting temperature (T m ) of the p53 mutant.
  • the melting point change may be recorded by differential scanning fluorimetry (DSF).
  • the change in melting point temperature (either positive or negative ⁇ T m ) may be at least 0.00, at least 0.01 , at least 0.05, at least 0.10, at least 0.20, at least 0.30, at least 0.40, at least 0.50, at least 0.60 °C.
  • the method is for stabilizing a p53 protein which carries a Y220C mutation, the method comprising bringing the p53 into contact with a compound of formula (I) as described herein. Such a method may be practiced in vitro, e.g. differential scanning fluorimetry, as described in the accompanying examples.
  • stabilizing p53 it is meant increasing the melting temperature of a p53 protein having a Y220C mutation, and/or increasing the half-life of such protein.
  • the compounds of the invention as defined in any one of (1 ) to (325), are for use in a method of increasing the stability (stabilising) of a p53 mutant.
  • the compound may increase the melting temperature of the p53 mutant.
  • the increase in melting point temperature i.e. positive ⁇ T m
  • the increase in melting point temperature is at least 0.01 , at least 0.05, at least 0.1 0, at least 0.20, at least 0.30, at least 0.40, at least 0.50, at least 0.60 °C.
  • the method of the invention may also be practiced on cells, e.g. in a cell culture of mammalian, such as human cells, wherein the cells express a p53 carrying the Y220C mutation.
  • the cells may be genetically engineered to express a human p53 Y220C protein in addition to, or in place of, the native p53 protein.
  • Cells in the culture may be primary cells, e.g. derived from a tumour of a human or non-human mammalian subject, or a cell line.
  • the above-described method may be practiced on a primary cell line or sample of a human lesion or tumour which has, or is suspected to have, a Y220C p53 protein, in order to determine the effectiveness of a compound of formula (I), as defined in any one of (1 ) to (325), in restoring or improving p53 function in the cell.
  • a compound of formula (I) as defined in any one of (1 ) to (325)
  • such an improvement or restoration may be marked by an increased rate of apoptosis in the cell culture compared to a culture of the same cells not treated with a compound of formula (I).
  • the invention may further comprise the step of administering to the subject from whom the sample was obtained the compound of formula (I), as defined in any one of (1 ) to (325).
  • lesion it is meant a non-cancerous growth of cells, e.g. such as a benign or pre-cancerous growth.
  • tumor it is meant any cancerous growth of a cell in which un-regulated cell division occurs at least in part as a result of the loss of p53 function caused by the presence of a Y220C mutation. In some instances, the mutation will be present together with one or more other mutations to other genes present in the cell, which will affect the growth and spread of the cancerous cells.
  • the invention may be administered to a mammalian subject, such as a human, in order to treat a lesion or a tumour which has a p53 Y220C mutation.
  • the invention will comprise administering to the subject an effective amount of a compound of formula (I) so as to improve or restore p53 function.
  • the invention further provides a method of determining the binding of a molecule to a p53 which carries a Y220C mutation, the method comprising bringing the molecule into contact with said p53 in competition with a compound, as defined in any one of (1 ) to (325), and measuring the binding or displacement of one or other of said compounds.
  • one or both of the compounds may carry a label, such as a radiolabel, chromophore, fluorophore or a fluorine function for competition-based 9 F-screening using magnetic resonance techniques.
  • a compound as defined in any one of (1 ) to (325), is provided with a label, such as a radiolabel, chromophore, fluorophore or a fluorine function for competition-based 9 F-screening using magnetic resonance techniques, it may be used as a probe to detect the presence of a p53 which carries a Y220C mutation, either in vivo or in vitro.
  • a label such as a radiolabel, chromophore, fluorophore or a fluorine function for competition-based 9 F-screening using magnetic resonance techniques
  • the compound in question stabilise the p53.
  • the compound for its use it may be sufficient that the compound bind to the p53 in order to be detected, or in order to be displaced in the competition assay.
  • Another aspect of the present invention pertains to a compound, as defined in any one of (1 ) to (325), for use in a method of treatment of the human or animal body by therapy.
  • the invention may be administered to a mammalian subject, such as a human, in order to treat a lesion or a tumour which has a p53 Y220C mutation.
  • Another aspect of the present invention pertains to use of a compound, as defined in any one of (1 ) to (325), in the manufacture of a medicament for use in treatment.
  • the medicament comprises a compound, as defined in any one of (1 ) to (325). In one embodiment, the medicament is for use in the treatment of a lesion or a tumour which has a p53 Y220C mutation.
  • Another aspect of the present invention pertains to a method of treatment comprising administering to a patient in need of treatment a therapeutically effective amount of a compound as defined in any one of (1 ) to (325), preferably in the form of a pharmaceutical composition.
  • Another aspect of the present invention pertains to a method for treating a cell in which p53 carries a Y220C mutation, the method comprising contacting the cell with a compound of formula (I) as defined in any one of (1 ) to (325).
  • Another aspect of the present invention pertains to a method for treating a subject who has a lesion or a tumour in which p53 carries a Y220C mutation, the method comprising contacting the cell with a compound of formula (I) as defined in any one of (1 ) to (325).
  • Another aspect of the present invention pertains to a method of determining the binding of a molecule to a p53 which carries a Y220C mutation, the method comprising bringing the molecule into contact with said p53 in competition with a compound of formula (I) as defined in any one of (1 ) to (325), and measuring the binding or displacement of one or other of said compounds.
  • the invention is not confined to any one particular type cell, but to any lesion or tumour in which p53 function is compromised by the presence of a Y220C mutation.
  • a Y220C mutation may be found, for example, in leukaemias,
  • lymphomas myelomas, plasmacytomas, and the like; and solid tumours.
  • solid tumours include but are not limited to colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, renal cell carcinoma, hepatoma, cervical cancer, testicular tumour, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, melanoma, neuroblastoma, and retinoblastoma.
  • the treatment is treatment of a solid tumour cancer, e.g., cancer of the bladder, breast cancer (female and / or male), colon cancer, kidney cancer, lung cancer, pancreatic cancer, prostate cancer, brain cancer, skin cancer, thyroid cancer, or melanoma, e.g., a solid tumour cancer, cancer of the bladder, breast cancer (female and / or male), colon cancer, kidney cancer, lung cancer, pancreatic cancer, prostate cancer, brain cancer, skin cancer, thyroid cancer, e.g., alone, or in combination with, and to augment the efficacy of, radiotherapy or chemotherapy.
  • a solid tumour cancer e.g., cancer of the bladder, breast cancer (female and / or male)
  • colon cancer cancer of the bladder, breast cancer (female and / or male
  • colon cancer cancer of the bladder, breast cancer (female and / or male)
  • colon cancer cancer of the bladder, breast cancer (female and / or male
  • colon cancer cancer of the bladder, breast cancer (fe
  • the treatment is treatment of a haematological malignancy, e.g., T-cell lymphoblastic lymphoma, mantle cell lymphoma, or acute
  • lymphoblastic leukemia e.g., a haematological malignancy, T-cell lymphoblastic lymphoma, mantle cell lymphoma, or acute lymphoblastic leukemia associated with inactivation or impairment of caspase induction or with aberrant caspase signalling, e.g., alone or in combination with, and to augment the efficacy of, radiotherapy or chemotherapy.
  • the treatment is treatment of a solid tumour cancer, e.g., renal cell carcinoma, breast cancer (female and / or male), gastric cancer, prostate cancer, colon cancer, or basal cell ameloblastoma, e.g., a solid tumour cancer, e.g., renal cell carcinoma, breast cancer (female and / or male), gastric cancer, prostate cancer, colon cancer, or basal cell ameloblastoma associated with inactivation or impairment of caspase induction or with aberrant caspase signalling, e.g., alone, or in combination with, and to augment the efficacy of, radiotherapy or chemotherapy.
  • a solid tumour cancer e.g., renal cell carcinoma, breast cancer (female and / or male)
  • gastric cancer e.g., prostate cancer, colon cancer
  • basal cell ameloblastoma associated with inactivation or impairment of caspase induction or with aberrant caspase signalling, e.g., alone, or in combination
  • the treatment is part of treatment by combination therapy, e.g., in combination with, and to augment the efficacy of, radiotherapy or chemotherapy.
  • treatment pertains generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, alleviation of symptoms of the condition, amelioration of the condition, and cure of the condition.
  • Treatment as a prophylactic measure i.e., prophylaxis
  • prophylaxis is also included.
  • treatment use with patients who have not yet developed the condition, but who are at risk of developing the condition, is encompassed by the term "treatment.”
  • therapeutically-effective amount pertains to that amount of a compound, or a material, composition or dosage form comprising a compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.
  • treatment includes combination treatments and therapies, in which two or more treatments or therapies are combined, for example, sequentially or simultaneously.
  • treatments and therapies include, but are not limited to, chemotherapy (the administration of active agents, including, e.g., drugs, antibodies (e.g., as in immunotherapy), prodrugs (e.g., as in photodynamic therapy, GDEPT, ADEPT, etc.); surgery; radiation therapy; and gene therapy.
  • kits comprising (a) a compound as defined in any one of (1 ) to (325), or a composition comprising a compound as defined in any one of (1 ) to (325), e.g., preferably provided in a suitable container and/or with suitable packaging; and (b) instructions for use, e.g., written instructions on how to administer the compound or composition.
  • the written instructions may also include a list of indications for which the compound as defined in any one of (1 ) to (325) is a suitable treatment.
  • the compound or pharmaceutical composition comprising the compound as defined in any one of (1 ) to (325) may be administered to a subject by any convenient route of administration, whether systemically/peripherally or topically (i.e., at the site of desired action).
  • Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual ; transdermal (including, e.g., by a patch, plaster, etc.);
  • transmucosal including, e.g., by a patch, plaster, etc.
  • intranasal e.g., by nasal spray
  • ocular e.g., by eyedrops
  • pulmonary e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose
  • rectal e.g., by suppository or enema
  • vaginal e.g., by pessary
  • parenteral for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular,
  • a depot or reservoir for example, subcutaneously or intramuscularly.
  • the invention may be practiced on a non-human animal in which a human p53 Y220C cell line is present.
  • a human p53 Y220C cell line may be a xenograft cell line or the non-human animal may be a transgenic non-human mammal in which their p53 gene is replaced by a human Y220C p53 gene.
  • the gene may be linked to a promoter that is activatable, e.g. in a temporal fashion (i.e. at a certain point in development), in a cell-specific manner or by being induced (e.g. a tetracycline-inducible promoter).
  • a non-human mammal may be a rodent.
  • Rodents include rats, mice, guinea pigs, chinchillas and other similarly-sized small rodents used in laboratory research.
  • the subject/patient may be a chordate, a vertebrate, a mammal, a placental mammal, a marsupial (e.g., kangaroo, wombat), a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig), ovine (e.g., a sheep), bovine (e.g.,
  • the subject/patient may be any of its forms of development, for example, a foetus.
  • the subject/patient is a human.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) as defined in any one of (1 ) to (325) together with a pharmaceutically acceptable carrier.
  • composition, preparation, medicament comprising at least one compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, including, but not limited to, pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, antioxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents.
  • the formulation may further comprise other active agents, for example, other therapeutic or prophylactic agents.
  • the present invention further provides pharmaceutical compositions, as defined above, and methods of making a pharmaceutical composition comprising admixing at least one compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, e.g., carriers, diluents, excipients, etc. If formulated as discrete units (e.g., tablets, etc.), each unit contains a predetermined amount (dosage) of the compound.
  • pharmaceutically acceptable pertains to compounds, ingredients, materials, compositions, dosage forms, etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject in question (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • Each carrier, diluent, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.
  • Suitable carriers, diluents, excipients, etc. can be found in standard
  • the formulations may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the compound with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the compound with carriers (e.g., liquid carriers, finely divided solid carrier, etc.), and then shaping the product, if necessary.
  • carriers e.g., liquid carriers, finely divided solid carrier, etc.
  • the formulation may be prepared to provide for rapid or slow release; immediate, delayed, timed, or sustained release; or a combination thereof.
  • Formulations may suitably be in the form of liquids, solutions (e.g., aqueous, non- aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in- water, water-in-oil), elixirs, syrups, electuaries, mouthwashes, drops, tablets (including, e.g., coated tablets), granules, powders, losenges, pastilles, capsules (including, e.g., hard and soft gelatin capsules), cachets, pills, ampoules, boluses, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, mists, or aerosols.
  • solutions e.g., aqueous, non- aqueous
  • suspensions e.g., aqueous, non-aqueous
  • Formulations may suitably be provided as a patch, adhesive plaster, bandage, dressing, or the like which is impregnated with one or more compounds and optionally one or more other pharmaceutically acceptable ingredients, including, for example, penetration, permeation, and absorption enhancers. Formulations may also suitably be provided in the form of a depot or reservoir.
  • the compound may be dissolved in, suspended in, or admixed with one or more other pharmaceutically acceptable ingredients.
  • the compound may be presented in a liposome or other microparticulate which is designed to target the compound, for example, to blood components or one or more organs.
  • Formulations suitable for oral administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non- aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, tablets, granules, powders, capsules, cachets, pills, ampoules, boluses.
  • Formulations suitable for buccal administration include mouthwashes, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.
  • Losenges typically comprise the compound in a flavoured basis, usually sucrose and acacia or tragacanth.
  • Pastilles typically comprise the compound in an inert matrix, such as gelatin and glycerin, or sucrose and acacia.
  • Mouthwashes typically comprise the compound in a suitable liquid carrier.
  • Formulations suitable for sublingual administration include tablets, losenges, pastilles, capsules, and pills.
  • Formulations suitable for oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, nonaqueous), emulsions (e.g., oil-in-water, water-in-oil), mouthwashes, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.
  • solutions e.g., aqueous, non-aqueous
  • suspensions e.g., aqueous, nonaqueous
  • emulsions e.g., oil-in-water, water-in-oil
  • mouthwashes e.g., losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.
  • Formulations suitable for non-oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, nonaqueous), emulsions (e.g., oil-in-water, water-in-oil), suppositories, pessaries, gels, pastes, ointments, creams, lotions, oils, as well as patches, adhesive plasters, depots, and reservoirs.
  • solutions e.g., aqueous, non-aqueous
  • suspensions e.g., aqueous, nonaqueous
  • emulsions e.g., oil-in-water, water-in-oil
  • suppositories e.g., pessaries, gels, pastes, ointments, creams, lotions, oils, as well as patches, adhesive plasters, depots, and reservoirs.
  • Formulations suitable for transdermal administration include gels, pastes, ointments, creams, lotions, and oils, as well as patches, adhesive plasters, bandages, dressings, depots, and reservoirs.
  • Tablets may be made by conventional means, e.g., compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g., povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silica);
  • binders e.g., povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose
  • fillers or diluents e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate
  • lubricants e
  • disintegrants e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose
  • surface-active or dispersing or wetting agents e.g., sodium lauryl sulfate
  • preservatives e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid
  • flavours e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid
  • flavours e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid
  • flavours e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid
  • flavours e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid
  • flavours e.g., methyl p-hydroxybenzo
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the compound therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with a coating, for example, to affect release, for example an enteric coating, to provide release in parts of the gut other than the stomach.
  • Ointments are typically prepared from the compound and a paraffinic or a water- miscible ointment base.
  • Creams are typically prepared from the compound and an oil-in-water cream base.
  • the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1 ,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof.
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the compound through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues.
  • Emulsions are typically prepared from the compound and an oily phase, which may optionally comprise merely an emulsifier (otherwise known as an emulgent), or it may comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
  • an emulsifier also known as an emulgent
  • a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat.
  • the emulsifier(s) with or without stabiliser(s) make up the so-called emulsifying wax
  • the wax together with the oil and/or fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • Suitable emulgents and emulsion stabilisers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.
  • suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the compound in most oils likely to be used in pharmaceutical emulsion formulations may be very low.
  • the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • Formulations suitable for intranasal administration, where the carrier is a liquid include, for example, nasal spray, nasal drops, or by aerosol administration by nebuliser, include aqueous or oily solutions of the compound.
  • Formulations suitable for intranasal administration, where the carrier is a solid include, for example, those presented as a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Formulations suitable for pulmonary administration include those presented as an aerosol spray from a pressurised pack, with the use of a suitable propellant, such as
  • dichlorodifluoromethane trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.
  • Formulations suitable for ocular administration include eye drops wherein the compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the compound.
  • Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, for example, cocoa butter or a salicylate; or as a solution or suspension for treatment by enema.
  • a suitable base comprising, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, for example, cocoa butter or a salicylate; or as a solution or suspension for treatment by enema.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the compound, such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous or non-aqueous, isotonic, pyrogen-free, sterile liquids (e.g., solutions, suspensions), in which the compound is dissolved, suspended, or otherwise provided (e.g., in a liposome or other microparticulate).
  • Such liquids may additional contain other pharmaceutically acceptable ingredients, such as anti- oxidants, buffers, preservatives, stabilisers, bacteriostats, suspending agents, thickening agents, and solutes which render the formulation isotonic with the blood (or other relevant bodily fluid) of the intended recipient.
  • excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like.
  • suitable isotonic carriers for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's
  • the concentration of the compound in the liquid is from about 1 ng/mL to about 100 g/mL, for example from about 1 0 ng/mL to about 10 g/mL, for example from about 10 ng/mL to about 1 ⁇ g/mL.
  • the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
  • the invention will comprise administering to the subject an effective amount of a compound of formula (I) as defined in any one of (1 ) to (325) so as to improve or restore p53 function.
  • appropriate dosages of the compounds, and compositions comprising the compounds can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects.
  • the selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound as defined in any one of (1 ) to (325), the route of administration, the time of administration, the rate of excretion of the compound as defined in any one of (1 ) to (325), the duration of the treatment, other drugs, compounds, and/or materials used in combination, the severity of the condition, and the species, sex, age, weight, condition, general health, and prior medical history of the patient.
  • the amount of compound as defined in any one of (1 ) to (325) and route of administration will ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage will be selected to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.
  • Administration can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment.
  • Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell(s) being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician, veterinarian, or clinician.
  • a suitable dose of the compound as defined in any one of (1 ) to (325) is in the range of about 10 ⁇ g to about 250 mg (more typically about 1 00 ⁇ g to about 25 mg) per kilogram body weight of the subject per day.
  • the compound is a salt, an ester, an amide, a prodrug, or the like
  • the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.
  • administering in conjunction with other anti-cancer agents.
  • Administration may be simultaneous, separate or sequential.
  • simultaneous administration it is meant that the compound of formula (I) and a second anti-cancer agent are administered to a subject in a single dose by the same route of administration.
  • sequential it is meant that the two agents are administered at different points in time, provided that the activity of the first administered agent is present and ongoing in the subject at the time the second agent is administered.
  • another anti-cancer agent may be administered first, such that tumour cells in the subject are damaged, followed by administration of the compound of formula (I) such that p53 function is provided to induce apoptosis.
  • a sequential dose will occur such that the second of the two agents is administered within 48 hours, preferably within 24 hours, such as within 1 2, 6, 4, 2 or 1 hour(s) of the first agent.
  • the amount of the compound of formula (I) as defined in any one of (1 ) to (325) to be administered to a subject will ultimately depend upon the nature of the subject and the disease to be treated.
  • the second therapeutic compound may be an anti-cancer agent which is a chemotherapeutic agent, an apoptosis-inducing agent, a cytotoxin, a steroid, an antimetabolite, an anthracycline, a vinca alkaloid, an antibiotic, a chemokine, a topoisomerase inhibitor, taxane, a DNA cross-linking agent, an intercalating agent, a microtubule-directed agent, a kinase inhibitor, a farnesyl transferase inhibitor, a hormone, a hormone antagonist, a DNA fragmenting agent, a protein synthesis inhibitor, a glucocorticoid, a LHRH antagonist or an alkylating agent.
  • Reference to compounds of formula (I) as defined in any one of (1 ) to (325) in the above, and herein below, is to be understood to include any compound covered by this definition including preferred subsets of these compounds, unless explicitly stated to the contrary.
  • the second anti-cancer agent is selected from
  • gemcitabine taxol, vincristine, vinblastine, a combretastatin, doxorubicin, etoposide, actinomycin-D, docetaxel, cyclophosphamide, edelfosine,
  • the second anti-cancer agent is selected from angiostatin, endostatin, a 16 kDa prolactin fragment, a laminin peptide, a fibronectin peptide, a tissue metalloproteinase inhibitor, a plasminogen activator inhibitor, TGF- ⁇ , IFN- ⁇ , IFN- ⁇ , an ELR-CXC chemokine, SDF-1 , MIG, platelet factor 4, IP-1 0, thrombospondin, SPARC, 2-Methoxyoestradiol, proliferin-related protein, suramin, thalidomide, cortisone, linomide, fumagillin, a retinoid, CM1 01 , dexarnethasone and leukemia inhibitory factor.
  • the second anti-cancer agent is an anti-tubulin drug, a calcium flux inducing agent, a calcium ionophore or an inflammatory cytokine.
  • the second anti-cancer agent is an antibody or an antigen- binding fragment thereof (e.g. a scFv, Fv, Fab', Fab, diabody, linear antibody or F(ab') 2 antigen-binding fragment) that binds to a tumour cell, an intracellular antigen released from a necrotic tumor cell or to a component of tumour vasculature.
  • an antigen- binding fragment thereof e.g. a scFv, Fv, Fab', Fab, diabody, linear antibody or F(ab') 2 antigen-binding fragment
  • the second anti-cancer agent is taxol, vincristine, vinblastine, neomycin, a podophyllotoxin, TNF-a, angiostatin, endostatin, vasculostatin, a calcium-flux inducing agent or a calcium ionophore.
  • the second anti-cancer agent is a combretastatin, paclitaxol or docetaxel.
  • the second agent is an agent that alters the activity of a protein within the p53 pathway.
  • the second agent may be used in combination with a compound of formula (I), as defined in any of (1 ) to (325), to regulate one or more transduction pathways involved in apoptosis.
  • proteins that may be targeted by the second agent include MDM2 (murine double minute) and MDMX, as well as a CREB (CAMP responsive element binding protein) protein.
  • pk5151 1 - ⁇ 1 -[(3,5-dichloro-2-hydroxyphenyl)methyl]piperidin-4-yl ⁇ piperidin-4-ol pk5152 2- ⁇ [2-(3-bromophenyl)pyrrolidin-1 -yl]methyl ⁇ -4,6-diiodophenol pk5153 2- ⁇ [3-(2-hydroxyethyl)-4-methylpiperazin-1 -yl]methyl ⁇ -4,6-diiodophenol pk5154 2- ⁇ [2-(hydroxymethyl)pyrrolidin-1 -yl]methyl ⁇ -4,6-diiodophenol pk5155 1 -[(2-hydroxy-3,5-diiodophenyl)methyl]-3-methylpiperidin-3-ol pk5156 (3R,4R)-1 -[(2-hydroxy-3,5-diiodophenyl)methyl]pyrrolidine-3,4-diol pk5157
  • the present invention provides a method of preparing compound of formula (X):
  • A, -Ri , -R 2 , -R 3 , -R 4 , and -R 8 are as defined in any one of (1 ) to
  • -R 2 , -R3, and -R 8 are as defined in any one of (1 ) to (325), if present.
  • A, -Ri , -R 2 , -R 3 , -R 4 , and -R 8 A are as defined in any one of (1 ) to (325), if present.
  • -R 2 , -R3, and -R 8 are as defined in any one of (1 ) to (325), if present.

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Abstract

La présente invention concerne des composés utilisables dans une méthode de traitement d'un patient souffrant d'une lésion ou d'une tumeur dans laquelle p53 porte une mutation Y220C. Les composés sont choisis parmi les composés de formule (I) suivante et leurs sels, hydrates ou solvates pharmaceutiquement acceptables : (I) R : où A est CR4 ou N ; -R-1 est choisi parmi -OH, -OMe, -NH2, -SH, -F et -CF3 ; -R2 est choisi parmi -CI, -Br, -I et l'éthynyle (-C≡CH) ; -R3 est choisi parmi -I, -Br, -CI, l'éthynyle (-C≡CH), -R35, -H, -OMe et -NO2 ; -R3S étant choisi parmi : formule IIa, formule IIb, formule IIc, et -R5 étant choisi parmi -COOH et : formule IIIa, formule IIIb, formule IIIc, où -R6, -R7A, - R7B, -Rs et -R8A sont tels que définis dans le mémoire. L'invention concerne également les composés de formule (I), leur utilisation dans des méthodes de traitement et des procédés pour les préparer.
PCT/GB2012/051428 2011-06-20 2012-06-20 Composés permettant de stabiliser les mutants de p53 Ceased WO2012175962A1 (fr)

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