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WO2015028929A1 - Composés et composition pouvant être utilisés pour inhiber l'intéraction lbc-rhoa, en particulier pour le traitement du cancer - Google Patents

Composés et composition pouvant être utilisés pour inhiber l'intéraction lbc-rhoa, en particulier pour le traitement du cancer Download PDF

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Publication number
WO2015028929A1
WO2015028929A1 PCT/IB2014/064049 IB2014064049W WO2015028929A1 WO 2015028929 A1 WO2015028929 A1 WO 2015028929A1 IB 2014064049 W IB2014064049 W IB 2014064049W WO 2015028929 A1 WO2015028929 A1 WO 2015028929A1
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cooh
lbc
rhoa
compound
compounds
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Francesca FANELLI
Francesco RAIMONDI
Dario DIVIANI
Damiano DEL VESCOVO
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Universite de Lausanne
Universita Degli Studi di Modena e Reggio Emilia
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Universite de Lausanne
Universita Degli Studi di Modena e Reggio Emilia
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    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • 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
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to compounds of formula (III) and/or salts thereof, or compounds of formula (IV) and/or salts thereof for use in the inhibition of the Lbc-RhoA interaction and to the pharmaceutical compositions comprising the same:
  • the present invention relates to compounds of formula (III) and/or salts thereof, or compounds of formula (IV) and/or salts thereof for use in the inhibition of the Lbc-RhoA interaction and to the pharmaceutical compositions comprising the same:
  • the present invention relates also to compounds of formula (III) and/or salts thereof, or compounds of formula (IV) and/or salts thereof for use in the treatment of cancer and to the pharmaceutical compositions comprising the same.
  • Rho (Ras homolog) proteins comprise a main family of the Ras superfamily of small GTPases (ref . 1) . They function as bi-molecular switches by adopting different conformational states in response to binding GDP or GTP .
  • Rho-GDP In contrast to Rho-GDP, Rho-GTP actively transduces signals by interacting with downstream effectors, which mediate a range of different cellular functions including cell-cycle progression and gene transcription, adhesion and migration, phagocytosis, cytokinesis, neurite extension and retraction, cellular morphogenesis and polarization, growth and cell survival (ref. 2) .
  • GTPase activating proteins GTPase activating proteins
  • GEFs guanine nucleotide- exchange factors
  • RhoGEFs 69 distinct members, share a catalytic domain homologous to that of the Dbl oncoprotein (DH domain, Figure 1) (ref . 3) .
  • Dbl-family GEFs are not the sole activators of Rho GTPases.
  • the DH domain is positioned immediately N- terminal to a pleckstrin homology (PH) domain ( Figure 1A and IB) . Structures of PH/DH tandem domains from several RhoGEFs have been determined either alone or in complex with their substrate GTPases (i.e. available from the Protein Data Bank (http://www.rcsb.org)) .
  • Leukemia-associated RhoGEF (LARG) and its close homologues, A-kinase anchoring protein-Lbc (AKAP- Lbc) , PDZ-RhoGEF (PDZ)and pll5-RhoGEF (pll5), are RhoA- selective RhoGEFs that are directly regulated by activated Goii2/i3 proteins (i.e. only G0C12 in the case of AKAP-Lbc) and are suggested to play a role in oncogenic transformations induced by G protein-coupled receptors (GPCRs) (ref . 5-9) .
  • GPCRs G protein-coupled receptors
  • Rho GTPases play important roles in many aspects of cancer development and tumor progression (ref. 10-11) . Therefore, inhibiting the activation of individual Rho GTPases by their specific GEFs might represent an attractive strategy to impair Rho signaling in cancer cells.
  • the oncogenic function of the RhoGEF AKAP-Lbc hereinafter referred to as Lbc, was discovered a number of years ago (ref. 12) . Later on, several lines of evidence have shed new light on the potential role of Lbc in the process of tumor development (ref. 13-20) .
  • the main goal of this invention is to suppress oncogenic signals promoted by Lbc by means of small molecules that could specifically impair the ability of Lbc to bind and activate RhoA.
  • HTVS high-throughput virtual screening
  • RhoGEF LARG have appeared over the last two years, supporting the validity of the present strategy (ref. 21-24) .
  • our invention consists in small molecules able to compete with RhoA in interacting with Lbc (i.e. protein-protein interaction inhibitors (PPI)) .
  • PPI protein-protein interaction inhibitors
  • Figure 1 Predicted structure of Lbc: identification of a hot region for RhoA activation, which was used as a target of compound screening.
  • Figure 2 Compounds sent to in vitro testing after virtual screening on 850000 negatively charged compounds from the ZINC database.
  • Figure 3 Compounds A13 and A21 inhibit Lbc-RhoA interaction .
  • Figure 5 - A13 and A21 show overlapping modes of interaction with the DH domain of Lbc.
  • Figure 6 Dose-response curves determining the half maximal concentration of A13 able to inhibit Lbc- RhoA interaction and Lbc-induced RhoA activation in intact cells.
  • Figure 8 Inhibitions of the ability of Lbc to induce stress fiber formation and cell transformation in NIH-3T3 fibroblasts using compound A13.
  • Figure 9 - A13 blocks migration of prostate cancer cells .
  • 655 compounds passed one of the filters as sharing a docking score ⁇ -9 kcal/mole.
  • Said thirty compounds are structurally dissimilar with the exception of compounds A07 and A10, selected for their docking score and, to a lesser extent, A13 and A29, which share a common fragment (see Figure 2) .
  • GST-Pulldown experiments on cell lysates determined the ability of compounds to inhibit the interaction between Lbc and RhoA. Extracts of HEK-293 cells overexpressing Flag-tagged Lbc were incubated with purified GST-tagged RhoA in the absence or presence of ⁇ of the selected compounds.
  • One compound, A13 was able to inhibit by more than 90% the binding of Lbc to GST-RhoA ( Figures 2 and 3) .
  • both the benzoic acid and pyrazole moieties of compound A13 holding the structural formula (I) interact with the K2152 hotspot, the carboxylate in R2 (see the structural formulas in Figure 4) making also a H-bond with T2151.
  • the other phenyl ring docks into a cavity formed by T2005, R2011, R2135, L2137, C2142 and L2145; the latter interacts with the CF3 group ( Figure IB) .
  • the partially active A21 holding the structural formula (II)
  • the furane ring overlaps with the pyrazol ring of A13; b) the phenyl ring of the benzoic acid overlaps with the phenyl ring of the benzoic acid of A13, the carboxylate making a salt bridge with K2152 that is also involved in H-bond with the furyl oxygen atom; c) the pyrimidinylidene ring partially overlaps with the furane ring of A13; and d) finally, the naphthalene moiety docks into the same cavity recognized by the trifluoromethyl-substituted phenyl ring of A13 ( Figure 5) .
  • RhoA RhoA binding with LARG and PDZ but not with pll5 (see Figure 4) .
  • an alkyl-amide e.g. - (CH 2 ) 2 CONH 2 , - (CH 2 ) 3 CONH 2
  • a protonated alkyl-amine e.g. - (CH 2 ) 3 NH 3 +
  • a protonated alkyl-guanidine e.g. - (CH 2 ) 3 NHC (NH 2 ) 2 +
  • the main information that emerges from SAR analysis is that, when R4 and R5 are unsubstituted (e.g. they hold a hydrogen atom), a negatively charged group (e.g. a carboxylate) favors the PPI activity more than neutral and lipophilic substituents (e.g. -CH 3 , -COOCH (CH 3 ) 2 , -CI) .
  • a negatively charged group e.g. a carboxylate
  • the predicted docking mode between A13 and Lbc suggests that the following substituents are worth probing: a) a carboxylate in R7 as an alternative to the carboxylate in either Rl or R2 ; b) a carboxylate group (e.g. (CH 2 ) 2 COO-, or - ( CH 2 ) 3 -COO ⁇ ) at either R8 or R9, better R8; and c) a carboxylate group (e.g. -(CH 2 ) 2 COO-, or - (C3 ⁇ 4) 3-COCT) in RIO as an alternative to the carboxylate in R6.
  • a carboxylate in R7 as an alternative to the carboxylate in either Rl or R2 ;
  • a carboxylate group e.g. (CH 2 ) 2 COO-, or - ( CH 2 ) 3 -COO ⁇
  • RIO e.g. -(CH 2 ) 2 COO-, or - (C3 ⁇ 4) 3-
  • An object of the present invention are compounds of the general formula (III) and/or salts thereof for use in the inhibition of the Lbc-RhoA interaction:
  • Ri is selected in the group consisting of -H, COOH and -S0 2 NH 2 ; preferably Ri is -H when R 2 is -COOH or Ri is -COOH when R 2 is -H;
  • R 2 is selected in the group consisting of -H,
  • R 2 is -H when RI is COOH or R 2 is -COOH when R x is -H;
  • R3 is selected in the group consisting of C 1 -C4 alkyl, halogenated C 1 -C4 alkyl, C 2 -C alkylamides (preferably primary alkylamides), C3-C4 alkylamines (preferably primary alkylamines) and C 2 -C3 alkylguanidines ; preferably R3 is C 1 -C4, alkyl halogenated C 1 -C4 alkyl or C3-C4 alkylamines, and, more preferably, R 3 is -CH 3 or -CF 3 ;
  • R4 is selected in the group consisting of -H, C 1 -C4 alkyl, halogenated C 1 -C4 alkyl, halogen and -N0 2 ; preferably R4 is -H or -F;
  • R5 is selected in the group consisting of -H, COOH, -S0 2 NH 2 , halogen, -CF 3 , -C(CH 3 ) 3 and -COOR, wherein R is -CH 3 , -C 2 3 ⁇ 4 or C 1 -C4 alkyl; preferably R5 is -H, -COOCH3, -COOC 2 H 5 , -CF 3 or -C(CH 3 ) 3 ;
  • R6 is selected in the group consisting of -H, COOH, halogen, C 1 -C4 alkyl, C 1 -C4 alkyl ether, -S0 2 NH 2 and -COOR, wherein R is -CH 3 , -C 2 H 5 or C 1 -C4 alkyl; preferably R 6 is -H, -COOH or CI;
  • R 7 is H, -COOH or -S0 2 NH 2 ; preferably, R 7 is H when Ri or R 2 is -COOH or R 7 is -COOH when R x and R 2 are both H;
  • Rs and R9 may be H or - (CH 2 ) n -COOH, wherein n ranges from 1 to 3, preferably Rs and R9 are not simultaneously carboxylate-holding substituents;
  • Rio is H, -COOH or -CH 2 -COOH.
  • compounds A13 and its structural analogs named as A33, A38, A40, A43, A45, A46, A13-S5 and A13-S6 and/or salts thereof are particularly preferred compounds for use in the inhibition of the Lbc-RhoA interaction.
  • the meaning of Ri to Rio for said preferred compounds are:
  • R x is H;
  • R 2 is COOH;
  • R 3 is CH 3 ;
  • R 4 is H;
  • R 5 is CF 3 ;
  • R 6 is H; each of R 7 , R 8 , R9 and Rio is H;
  • R x is H;
  • R 2 is COOH;
  • R 3 is CF 3 ;
  • R 4 is H;
  • R 5 is H;
  • R 6 is COOH; each of R 7 , R 8 , R 9 and Rio is H;
  • R x is H;
  • R 2 is COOH;
  • R 3 is CH 3 ;
  • R 4 is H;
  • R 5 is COOC2H5;
  • R 6 is CI; each of R 7 , R 8 , R 9 and Rio is H;
  • R x is H;
  • R 2 is COOH;
  • R 3 is CF 3 ;
  • R 4 is H;
  • R 5 is COOCH 3 ;
  • R 6 is H;
  • each of R 7 , R 8 , R 9 and Rio is H;
  • R x is H;
  • R 2 is COOH;
  • R 3 is CH 3 ;
  • R 4 is F;
  • R 5 is H;
  • R 6 is H; each of R 7 , R 8 , R9 and Rio is H;
  • R x is COOH;
  • R 2 is H;
  • R 3 is CH 3 ;
  • R 4 is H;
  • R 5 is CF 3 ;
  • R 6 is H; each of R 7 , R 8 , R9 and Rio is H;
  • R x is COOH;
  • R 2 is H;
  • R 3 is CH 3 ;
  • R 4 is H;
  • R 5 is COOCH 3 ;
  • R 6 is H; each of R 7 , R 8 , R 9 and Rio is H;
  • R x is H; R 2 is COOH; R 3 is CH 3 ; R 4 is H; R 5 is C(CH 3 ) 3 ; each of R6, R 7 , R 8 , R9 and Rio is H.
  • An object of the present invention are the pharmaceutical compositions comprising the compounds of general formula (III) and/or salts thereof, in particular compounds named A13, and its structural analogs named as A33, A38, A40, A43, A45, A46, A13-S5 and A13-S6 for use in the inhibition of the Lbc-RhoA interaction.
  • Objects of the present invention are compounds of the general formula (III) and/or salts thereof, in particular compounds A13 and its structural analogs named as A33, A38, A40, A43, A45, A46, A13-S5 and A13- S6 for use in the treatment of cancer, preferably in the treatment of prostate cancer.
  • compositions comprising the compounds of general formula (III) and/or salts thereof, in particular compounds named A13 and its structural analogs named as A33, A38, A40, A43, A45, A46, A13-S5 and A13-S6 for use in the treatment of cancer, preferably in the treatment of prostate cancer.
  • Objects of the present inventions are compounds of general formula (IV) and/or salts thereof, for use in the inhibition of the Lbc-RhoA interaction:
  • Ri is selected in the group consisting of -COOH and C 1 -C4 alkyl carboxylic acid.
  • Particularly preferred compounds according to formula (IV) are compound A21, wherein Ri is -COOH and its structural analogs.
  • An object of the present invention are the pharmaceutical compositions comprising the compounds of general formula (IV) and/or salts thereof, in particular compound named A21 and its structural analogs, for use in the inhibition of the Lbc-RhoA interaction .
  • Objects of the present invention are compounds of the general formula (IV) and/or salts thereof, in particular compound named A21 and its structural analogs, for use in the treatment of cancer.
  • Another object of the present invention are the pharmaceutical compositions comprising the compounds of the general formula (IV) and/or salts thereof, in particular compound named A21 and its structural analogs, for use in the treatment of cancer.
  • compositions of the present invention comprises the above identified compounds of general formula (III) or (IV) and are for the uses above defined. They can be in the form of pharmaceutically acceptable salts and complexes and can be provided in a pharmaceutically acceptable carrier and at an appropriate dose.
  • Such pharmaceutical compositions can be prepared by methods and contain carriers which are well-known in the art. A generally recognized compendium of such methods and ingredients is Remington: The Science and Practice of Pharmacy, Alfonso R. Gennaro, editor, 20th ed. Lippincott Williams & Wilkins: Philadelphia, Pa., 2000.
  • a pharmaceutically-acceptable carrier, composition or vehicle such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, is involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically-acceptable carrier, composition or vehicle such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, is involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject being treated.
  • Examples of materials which can serve as pharmaceutically acceptable carriers include sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • compositions of the present invention can be administered parenterally (for example, by intravenous, intraperitoneal, subcutaneous or intramuscular injection), topically (including buccal and sublingual), orally, intranasally, intravaginally, or rectally according to standard medical practices.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated and like factors well known in the medical arts .
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical compositions required.
  • the physician or veterinarian could start doses of a compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. This is considered to be within the skill of the artisan and one can review the existing literature on a specific compound or similar compounds to determine optimal dosing .
  • Figure 1 Predicted structure of Lbc: identification of a hot region for RhoA activation, which was used as target of compound screening.
  • A) cartoons of the predicted structure of Lbc are shown. The spheres centered on the C -carbons in the DH domain indicate the 12 amino acids out of the tested 33 playing an important role in RhoA recognition and or activation.
  • dark gray indicates those amino acids whose alanine substitution dramatically impairs both RhoA recognition and activation by Lbc.
  • lighter gray marks those amino acids whose alanine substitution moderately impairs RhoA recognition and activation or significantly impairs only RhoA activation by Lbc.
  • Figure 2 Compounds sent to in vitro testing after virtual screening on 850000 negatively charged compounds from the ZINC database. The effects of each compound on Lbc-RhoA binding is shown together with the mean ⁇ S.E. of three to eight independent experiments. See the legend to Figure 3 for more details on the experiments .
  • FIG. 3 Compounds A13 and A21 inhibit Lbc-RhoA interaction.
  • HEK-293 cells expressing Flag-tagged Lbc were serum starved for 24h and lysed.
  • Cell extracts were incubated with glutathione-sepharose beads coupled to GST-tagged RhoA in the presence of 1% DMSO (control) or ⁇ of 30 compounds identified by virtual screening and shown in Figure 2.
  • the relative levels of Flag-Lbc associated with GST-RhoA were detected by Western blot and quantified by densitometry. Results are the mean ⁇ S.E. of three to eight independent experiments .
  • Figure 5 - A13 and A21 show overlapping modes of interaction with the DH domain of Lbc.
  • the functionally relevant amino acids highlighted by alanine scanning mutagenesis are highlighted, colored according to the functional effect of their mutation (see the legend to Figure 1) .
  • A13 and A21 are black and light gray, respectively .
  • Figure 6 Dose-response curves determining the half maximal concentration of A13 able to inhibit Lbc- RhoA interaction and Lbc-induced RhoA activation in intact cells.
  • A) HEK-293 cells expressing Flag-tagged Lbc were serum starved for 24h and lysed. Cell extracts were incubated with glutathione-sepharose beads coupled to GST-tagged RhoA in the presence of 1% DMSO or increasing concentrations of A13. The relative levels of Flag-Lbc associated with GST-RhoA (upper panel) and expressed in cell extracts (middle panel) were detected by Western blot using anti-Flag monoclonal antibodies.
  • a control protein staining indicating the amounts of GST-RhoA used in the pulldown assay is shown (lower panel) .
  • GTP-bound RhoA was affinity purified from cell extracts using glutathione- sepharose beads coupled to GST-RBD.
  • RhoA was detected with a monoclonal anti-RhoA antibody (upper panel) .
  • the relative amounts of total RhoA and Flag-Lbc proteins in the cell lysates were assessed using monoclonal antibodies against RhoA (middle panel) and Flag (lower panels), respectively.
  • Figure 7 Effects of compound A13 on the interaction between RhoA and LARG, PDZ, and pll5.
  • A) HEK-293 cells expressing Flag-tagged Lbc, LARG, PDZ, and pll5 constructs were serum starved for 24h and lysed. Cell extracts were incubated with glutathione-sepharose beads coupled to GST-tagged RhoA in the absence (control) or presence of ⁇ of A13. The relative levels of Lbc, LARG, PDZ, and pll5 proteins associated with GST-RhoA (upper panel) and expressed in cell extracts (middle panel) were detected by Western blot using anti-Flag monoclonal antibodies.
  • a control protein staining indicating the amounts of GST-RhoA used in the pulldown assay is shown (lower panel) .
  • C IC50 values for the inhibitory effect of A13 on the interaction of Lbc, LARG, PDZ, and pll5 with RhoA. Data are reported as mean IC50 values ⁇ S.E. of three independent experiments.
  • Figure 8 inhibitions of the ability of Lbc to induce stress fiber formation and cell transformation in NIH-3T3 fibroblasts using compound A13.
  • This panel shows the results of the focus formation assay of NIH 3T3 cells stably transfected with the empty pFlag vector (control) or with the cDNA encoding Flag-Lbc and subsequently treated in the absence or presence of ⁇ of A13. Focus formation was evaluated after 21 days of culture.
  • Figure 9 - A13 blocks migration of prostate cancer cells.
  • the scratch test was used to investigate the wound healing ability at Oh, 12h, 24h, 36h, and 48h.
  • PC3 cells were seeded in twelve-well plates and grown up to 80% confluence. The scratch was made by a pipet tip and pictures (objective 4X) were taken immediately (Oh) . Cells were allowed to close the damage for 48h while kept at 37 °C.
  • Compounds A13 and A2 (as a negative control) were added 12 h before the scratch in 10 ⁇ concentration. The results are the mean ⁇ S.E from three independent experiments.
  • P is ⁇ 0.05 when the three determinations in the presence of A13 are compared with the control group or with the determinations in the presence of A2.
  • the % of scratch area at 24h, 36h and 48h was, respectively, 19.6416.24, 1.8510.70, and 0.0010.00 in control conditions, 16.5114.56, 0.74+0.42 and 0.00+0.00 in the presence of the inactive compound A2, and 50.67+6.23, 42.1+7.80 and 28.21+10.24 in the presence of A13. This indicates that A13 inhibits cancer cell migration.
  • FIG 10 Sequence alignment between Lbc and LARG employed for the comparative modeling of Lbc.
  • Canonical -helices and ⁇ -strands are light gray and dark gray, respectively.
  • Lower-case letters indicate the amino acids of LARG that have been deleted to allow for the six-amino acid insertion on Lbc.
  • Bold letters indicate the 33 amino acids targeted by in vitro alanine scanning mutagenesis.
  • the black box sets the PH domain.
  • Asterisks indicate conserved amino acids.
  • Figure 11 RhoA binding properties of mutants in the DH domain of Lbc. (A, C, E, G) HEK-293 cells expressing either wild type or mutated Flag-tagged Lbc constructs were serum starved for 24h and lysed.
  • FIG 12 RhoA activating properties of mutants in the DH domain of Lbc.
  • A, C, E, G HEK-293 cells expressing either wild type or mutated Flag-tagged Lbc constructs were serum starved for 24h and lysed. Cell extracts were incubated with GST-RBD beads. The bound RhoA was detected with a monoclonal anti-RhoA antibody (upper panel) . The relative amounts of total RhoA and Flag-Lbc proteins in the cell lysates were assessed using monoclonal antibodies against RhoA (middle panel) and Flag (lower panels), respectively.
  • LVG Leukemia-associated Rho guanine nucleotide exchange factor
  • Example 1 Prediction of the structural model of the Lbc-RhoA complex by comparative modeling.
  • a structural model of the Lbc-RhoA complex was predicted by comparative modeling (by means of MODELLER http://salilab.org/modeller/), by using the crystal structure of the LARG-RhoA complex (PDB code: 1X86 (ref. 26)) as a template.
  • the percentage of amino acids that are chemico-physically similar or identical between template (LARG) and target (Lbc) proteins is 57%, whereas sequence identity over the DH-PH tandem domain is 28% (the identities in the DH and PH domains being, respectively, 29% and 27%) .
  • RhoA structure was explicitly present during comparative modeling of Lbc.
  • Lbc six-amino acid insertion at the C-terminal end of 2
  • the 856-859 amino acid stretch of LARG corresponding to the 2/ 3 loop (i.e. lower case characters in Figure 10)
  • the insertion was, hence, modeled as a two- turn elongation of 2, by adding external -helix restraints to the 2062-2069 Lbc stretch. It is worth noting, however, that this portion is not involved in the interface with RhoA, thus making the structural indeterminations quite acceptable.
  • the initial model of Lbc was achieved from the sequence alignment shown in Figure 10.
  • 100 Lbc models were built by randomizing all the Cartesian coordinates of standard residues in the initial model.
  • the model resulting from the optimal combination of low MODELLER Objective Function (i.e. the second lowest value out of the 100 computed) , low content of main chain torsion angles in bad conformation, and relatively high 3D- Profile score (i.e. an indicator of the degree of fit between primary sequence and fold) was selected for the analysis of the Lbc-RhoA interface and for HTVS of compound libraries.
  • the selected model was subjected to automatic adjustments of those side chain torsion angles (i.e. by means of the Quanta package (www.accelrys.com)) found in non-allowed conformation.
  • Lbc is made of a DH domain, characterized by six -helices organized in an up-down bundle architecture and a PH domain, characterized by a roll architecture made by seven antiparallel ⁇ -strands ( Figure 1A and Figure 10) .
  • the former participates in the binding pocket of W58, an inter- switch amino acid turned out to be essential for Lbc- RhoA interaction.
  • the E2141 Lbc -W58 RhoA and Q2148 Lbc -N41 RhoA pairs are also expected to contribute to Lbc-RhoA binding by H-bonding interactions.
  • the DH domain in particular the region targeted by virtual screening, is highly structurally similar in the predicted and X-ray structures.
  • the predicted interface between Lbc and RhoA is very similar as well to the crystallographic complex. Indeed the RMSDs computed on the main-chain atoms participating in the Lbc-RhoA interface is 1.11 A.
  • alanine scanning mutagenesis was performed to define the role of the DH amino acids participating in the Lbc-RhoA interface. 33 amino acids from oil, 3, 4/ 5 loop, 5, and 6 (see Figure 11), which constitute 86% of the DH surface buried by RhoA were targeted .
  • Example 2 evaluation of compound A13 on the proliferative r migratory and invasive property of PC-3 prostate cancer cells.
  • the binding constant of A13 to Lbc was measured as well by microscale thermophoresis that allows sensitive and quantitative analysis of the interaction between small molecules and proteins.
  • Cell lysates expressing GFP or GFP-tagged Lbc were incubated with concentrations of A13 ranging from InM to lOuM.
  • the tested compound is a 50% mixture of cis and trans forms.
  • an ad hoc synthesized mixture enriched in the cis isomer i.e. A13 cis, cis:trans 75:25
  • Lbc-GFP bound Lbc-GFP with a Kd of 0.9 uM, thus suggesting that the cis isomer might display higher affinity for Lbc than the trans isomer.
  • This result is consistent with A13 holding a cis configuration in the predicted docking pose.
  • Rho signaling by Lbc family Rho-GEFs plays a prominent role in the regulation of prostate cancer cell proliferation, migration and invasion. Based on these observations, it was initially assessed, by the Rhotekin RBD or PAKl-CRIB pulldown assays, if A13 could affect the activity of RhoA, RhoB, RhoC, Racl and Cdc42 in PC-3 prostate cancer cells. The obtained results indicate that incubation of PC-3 cells with 10 ⁇ of A13 inhibits RhoA by 60% and RhoC by 37%, without affecting RhoB, Racl, and Cdc42.
  • A13 shoots down the oncogenic properties of Lbc because of its ability to inhibit Lbc-RhoA recognition. More importantly, A13 is able to significantly reduce the tumorigenic potential of prostate cancer cells likely due of its multi-PPI activity towards the complexes between RhoA (also RhoC though to a significantly lesser extent) and RhoGEFs of the Lbc sub-family, i.e. Lbc, LARG, and PDZ .

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Abstract

Cette invention concerne des composés de formule (III) et/ou des sels de ceux-ci, ou des composés de formule (IV) et/ou des sels de ceux-ci pouvant être utilisés pour inhiber l'interaction Lbc-RhoA et des compositions pharmaceutiques les contenant : Formule (III) et Formule (IV). Des composés de formule (III) et/ou des sels de ceux-ci, ou des composés de formule (IV) et/ou des sels de ceux-ci pouvant être utilisés pour traiter le cancer et des compositions pharmaceutiques les contenant sont en outre décrits.
PCT/IB2014/064049 2013-08-26 2014-08-25 Composés et composition pouvant être utilisés pour inhiber l'intéraction lbc-rhoa, en particulier pour le traitement du cancer Ceased WO2015028929A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107537332A (zh) * 2016-06-29 2018-01-05 丰田自动车株式会社 电极用湿润造粒体的制造装置和制造方法
WO2019060260A1 (fr) * 2017-09-19 2019-03-28 Indiana University Research And Technology Corporation Composés inhibiteurs de xpa et leur utilisation
CN118878449A (zh) * 2024-07-23 2024-11-01 广东省中医院（广州中医药大学第二附属医院、广州中医药大学第二临床医学院、广东省中医药科学院） DC-Rhoin类似物及其制备方法和应用
EP4516790A1 (fr) * 2023-08-28 2025-03-05 The University Of Hong Kong Ciblage covalent de rhoa pour cancérothérapie
US12486246B2 (en) 2019-12-10 2025-12-02 The Trustees Of Indiana University Replication protein A (RPA)-DNA interaction inhibitors

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007059195A1 (fr) * 2005-11-14 2007-05-24 University Of Southern California Petites molecules de liaison a une integrine
US20070196395A1 (en) * 2003-12-12 2007-08-23 Mackerell Alexander Immunomodulatory compounds that target and inhibit the py'binding site of tyrosene kinase p56 lck sh2 domain
EP1905762A1 (fr) * 2005-05-30 2008-04-02 Genecare Research Institute Co., Ltd Dérivé de pyrazolone
WO2011085039A2 (fr) * 2010-01-05 2011-07-14 The Johns Hopkins University Utilisation d'inhibiteurs de l'histone acétyltransférase en tant que nouvelles thérapies anticancéreuses
WO2012065139A2 (fr) * 2010-11-11 2012-05-18 Board Of Regents, The University Of Texas System Inhibiteurs de entpd5

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005026127A1 (fr) * 2003-09-11 2005-03-24 Institute Of Medicinal Molecular Design. Inc. Inhibiteur d'inhibiteur-1 activateur de plasmogene

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070196395A1 (en) * 2003-12-12 2007-08-23 Mackerell Alexander Immunomodulatory compounds that target and inhibit the py'binding site of tyrosene kinase p56 lck sh2 domain
EP1905762A1 (fr) * 2005-05-30 2008-04-02 Genecare Research Institute Co., Ltd Dérivé de pyrazolone
WO2007059195A1 (fr) * 2005-11-14 2007-05-24 University Of Southern California Petites molecules de liaison a une integrine
WO2011085039A2 (fr) * 2010-01-05 2011-07-14 The Johns Hopkins University Utilisation d'inhibiteurs de l'histone acétyltransférase en tant que nouvelles thérapies anticancéreuses
WO2012065139A2 (fr) * 2010-11-11 2012-05-18 Board Of Regents, The University Of Texas System Inhibiteurs de entpd5

Non-Patent Citations (36)

* Cited by examiner, † Cited by third party
Title
"Remington: The Science and Practice of Pharmacy", 2000, LIPPINCOTT WILLIAMS & WILKINS
AITTALEB, M.; BOGUTH, C. A.; TESMER, J. J.: "Structure and function of heterotrimeric G protein-regulated Rho guanine nucleotide exchange factors", MOL PHARMACOL., vol. 77, 2009, pages 111 - 125
BAISAMY, L.; JURISCH, N.; DIVIANI, D.: "Leucine zipper-mediated homo-oligomerization regulates the Rho-GEF activity of AKAP-Lbc.", J BIOL CHEM., vol. 280, 2005, pages 15405 - 15412
BONUCCELLI, G.; CASIMIRO, M. C.; SOTGIA, F.; WANG, C.; LIU, M.; KATIYAR, S.; ZHOU, J.; DEW, E.; CAPOZZA, F.; DAUMER, K. M.: "Caveolin-1 (P132L), a common breast cancer mutation, confers mammary cell invasiveness and defines a novel stem cell/metastasis-associated gene signature", AM J PATHOL., vol. 174, 2009, pages 1650 - 1662
BOWERS E M ET AL: "Virtual Ligand Screening of the p300/CBP Histone Acetyltransferase: Identification of a Selective Small Molecule Inhibitor", CHEMISTRY AND BIOLOGY, CURRENT BIOLOGY, LONDON, GB, vol. 17, no. 5, 28 May 2010 (2010-05-28), pages 471 - 482, XP002697557, ISSN: 1074-5521, DOI: 10.1016/J.CHEMBIOL.2010.03.006 *
COLICELLI, J.: "Human RAS superfamily proteins and related GTPases", SCI STKE, 2004, pages RE13
DIVIANI, D.; ABUIN, L.; COTECCHIA, S.; PANSIER, L.: "Anchoring of both PKA and 14-3-3 inhibits the Rho-GEF activity of the AKAP-Lbc signaling complex", EMBO J., vol. 23, 2004, pages 2811 - 2820
DIVIANI, D.; SODERLING, J.; SCOTT, J. D.: "AKAP-Lbc anchors protein kinase A and nucleates Galpha 12-selective Rho-mediated stress fiber formation", J BIOL CHEM., vol. 276, 2001, pages 44247 - 44257
DIVIANI, D.; SODERLING, J.; SCOTT, J. D.: "AKAP-Lbc anchors protein kinase A and nucleates Galpha 12-selective Rho-mediated stress fiber formation", J. BIOL. CHEM., vol. 276, 2001, pages 44247 - 44257
DORJBAL DORJSUREN ET AL: "Diverse Small Molecule Inhibitors of Human Apurinic/Apyrimidinic Endonuclease APE1 Identified from a Screen of a Large Public Collection", PLOS ONE, vol. 7, no. 10, 23 October 2012 (2012-10-23), pages e47974, XP055159631, DOI: 10.1371/journal.pone.0047974 *
FEHER, L. Z.; POCSAY, G.; KRENACS, L.; ZVARA, A.; BAGDI, E.; POCSAY, R.; LUKACS, G.; GYORY, F.; GAZDAG, A.; TARKO, E.: "Amplification of thymosin beta 10 and AKAP13 genes in metastatic and aggressive papillary thyroid carcinomas", PATHOL ONCOL RES., vol. 18, 2012, pages 449 - 458, XP035035391, DOI: doi:10.1007/s12253-011-9467-7
FRIESLAND, A.; ZHAO, Y.; CHEN, Y. H.; WANG, L.; ZHOU, H.; LU, Q.: "Small molecule targeting Cdc42-intersectin interaction disrupts Golgi organization and suppresses cell motility", PROC NATL ACAD SCI U S A., vol. 110, 2013, pages 1261 - 1266
FUKUHARA, S.; CHIKUMI, H.; GUTKIND, J. S.: "Leukemia-associated Rho guanine nucleotide exchange factor (LARG) links heterotrimeric G proteins of the G(12) family to Rho", FEBS LETT., vol. 485, 2000, pages 183 - 188, XP004337793, DOI: doi:10.1016/S0014-5793(00)02224-9
FUKUHARA, S.; MURGA, C.; ZOHAR, M.; IGISHI, T.; GUTKIND, J. S.: "A novel PDZ domain containing guanine nucleotide exchange factor links heterotrimeric G proteins to Rho.", J BIOL CHEM., vol. 274, 1999, pages 5868 - 5879, XP002111131, DOI: doi:10.1074/jbc.274.9.5868
GAO YUAN ET AL: "Rational design and characterization of a Rac GTPase-specific small molecule inhibitor", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, NATIONAL ACADEMY OF SCIENCES, US, vol. 101, no. 20, 18 May 2004 (2004-05-18), pages 7618 - 7623, XP002549221, ISSN: 0027-8424, [retrieved on 20040505], DOI: 10.1073/PNAS.0307512101 *
GAO, Y.; DICKERSON, J. B.; GUO, F.; ZHENG, J.; ZHENG, Y.: "Rational design and characterization of a Rac GTPase-specific small molecule inhibitor", PROC NATL ACAD SCI U S A., vol. 101, 2004, pages 7618 - 7623, XP002544661, DOI: doi:10.1073/PNAS.0307512101
HART, M. J.; JIANG, X.; KOZASA, T.; ROSCOE, W.; SINGER, W. D.; GILMAN, A. G.; STERNWEIS, P. C.; BOLLAG, G.: "Direct stimulation of the guanine nucleotide exchange activity of pll5 RhoGEF by Galpha13", SCIENCE, vol. 280, 1998, pages 2112 - 2114
HU, J. K.; WANG, L.; LI, Y.; YANG, K.; ZHANG, P.; CHEN, X. Z.; WANG, R.; ZHOU, Z. G.: "The mRNA and protein expression of A-kinase anchor proteins 13 in human colorectal cancer", CLIN EXP MED., vol. 10, 2010, pages 41 - 49, XP019764285
JAFFE, A. B.; HALL, A.: "Rho GTPases: biochemistry and biology", ANNU REV CELL DEV BIOL., vol. 21, 2005, pages 247 - 269
KARLSSON, R.; PEDERSEN, E. D.; WANG, Z.; BRAKEBUSCH, C.: "Rho GTPase function in tumorigenesis", BIOCHIM BIOPHYS ACTA, vol. 1796, 2009, pages 91 - 98, XP026639946, DOI: doi:10.1016/j.bbcan.2009.03.003
KRISTELLY, R.; GAO, G.; TESMER, J. J.: "Structural determinants of RhoA binding and nucleotide exchange in leukemia-associated Rho guanine-nucleotide exchange factor", J BIOL CHEM., vol. 279, 2004, pages 47352 - 47362
LEWIS, T. E.; MILAM, T. D.; KLINGLER, D. W.; RAO, P. S.; JAGGI, M.; SMITH, D. J.; HEMSTREET, G. P.; BALAJI, K. C.: "Tissue transglutaminase interacts with protein kinase A anchor protein 13 in prostate cancer", UROL ONCOL., vol. 23, 2005, pages 407 - 412, XP025311759, DOI: doi:10.1016/j.urolonc.2005.04.002
RAPONI, M.; HAROUSSEAU, J. L.; LANCET, J. E.; LOWENBERG, B.; STONE, R.; ZHANG, Y.; RACKOFF, W.; WANG, Y.; ATKINS, D.: "Identification of molecular predictors of response in a study of tipifarnib treatment in relapsed and refractory acute myelogenous leukemia", CLIN CANCER RES., vol. 13, 2007, pages 2254 - 2260, XP055103425, DOI: doi:10.1158/1078-0432.CCR-06-2609
RATHINAM, R.; BERRIER, A.; ALAHARI, S. K.: "Role of Rho GTPases and their regulators in cancer progression", FRONT BIOSCI., vol. 17, 2011, pages 2561 - 2571
RAVEENDRA DAYAM ET AL: "Discovery of Small Molecule Integrin [alpha] v [beta] 3 Antagonists as Novel Anticancer Agents - Supplementary Information", JOURNAL OF MEDICINAL CHEMISTRY, 1 January 2006 (2006-01-01), pages S1 - S3, XP055159633, Retrieved from the Internet <URL:http://pubs.acs.org/doi/suppl/10.1021/jm051296s/suppl_file/jm051296ssi20060526_064248.pdf> [retrieved on 20141219], DOI: 10.1021/jm051296s *
RAVEENDRA DAYAM ET AL: "Discovery of small molecule integrin alpha(v)beta(3) antagonists as novel anticancer agents", vol. 49, no. 15, 1 January 2006 (2006-01-01), pages 4526 - 4534, XP002674944, ISSN: 0022-2623, Retrieved from the Internet <URL:http://pubs.acs.org/doi/abs/10.1021/jm051296s> [retrieved on 20060701], DOI: 10.1021/JM051296S *
REN, X. D.; SCHWARTZ, M. A.: "Determination of GTP loading on Rho", METHODS ENZYMOL., vol. 325, 2000, pages 264 - 272
ROLLAND, D.; RIBRAG, V.; HAIOUN, C.; GHESQUIERES, H.; JARDIN, F.; BOUABDALLAH, R.; FRANCHI, P.; BRIERE, J.; DE KERVILER, E.; CHASS: "Phase II trial and prediction of response of single agent tipifarnib in patients with relapsed/refractory mantle cell lymphoma: a Groupe d'Etude des Lymphomes de l'Adulte trial", CANCER CHEMOTHER PHARMACOL., vol. 65, 2010, pages 781 - 790, XP019779242
ROSSMAN, K. L.; DER, C. J.; SONDEK, J.: "GEF means go: Turning on Rho GTPases with guanine nucleotide-exchange factors", NATURE REVIEWS MOLECULAR CELL BIOLOGY, vol. 6, 2005, pages 167 - 180
SHANG, X.; MARCHIONI, F.; EVELYN, C. R.; SIPES, N.; ZHOU, X.; SEIBEL, W.; WORTMAN, M.; ZHENG, Y.: "Small-molecule inhibitors targeting G-protein-coupled Rho guanine nucleotide exchange factors", PROC NATL ACAD SCI U S A., vol. 110, 2013, pages 3155 - 3160
SHANG, X.; MARCHIONI, F.; SIPES, N.; EVELYN, C. R.; JERABEK-WILLEMSEN, M.; DUHR, S.; SEIBEL, W.; WORTMAN, M.; ZHENG, Y.: "Rational design of small molecule inhibitors targeting RhoA subfamily Rho GTPases", CHEM BIOL., vol. 19, 2012, pages 699 - 710, XP028497233, DOI: doi:10.1016/j.chembiol.2012.05.009
SNYDER, J. T.; WORTHYLAKE, D. K.; ROSSMAN, K. L.; BETTS, L.; PRUITT, W. M.; SIDEROVSKI, D. P.; DER, C. J.; SONDEK, J.: "Structural basis for the selective activation of Rho GTPases by Dbl exchange factors", NAT STRUCT BIOL., vol. 9, 2002, pages 468 - 475, XP002447431, DOI: doi:10.1038/nsb796
STERPETTI, P.; MARUCCI, L.; CANDELARESI, C.; TOKSOZ, D.; ALPINI, G.; UGILI, L.; BARONI, G. S.; MACARRI, G.; BENEDETTI, A.: "Cell proliferation and drug resistance in hepatocellular carcinoma are modulated by Rho GTPase signals", AM J PHYSIOL GASTROINTEST LIVER PHYSIOL., vol. 290, 2006, pages G624 - 632
TOKSOZ, D.; WILLIAMS, D. A.: "Novel human oncogene lbc detected by transfection with distinct homology regions to signal transduction products", ONCOGENE, vol. 9, 1994, pages 621 - 628
TRACY M. NEHER ET AL: "Identification of Novel Small Molecule Inhibitors of the XPA Protein Using in Silico Based Screening", ACS CHEMICAL BIOLOGY, vol. 5, no. 10, 15 October 2010 (2010-10-15), pages 953 - 965, XP055159629, ISSN: 1554-8929, DOI: 10.1021/cb1000444 *
WIRTENBERGER, M.; TCHATCHOU, S.; HEMMINKI, K.; KLAES, R.; SCHMUTZLER, R. K.; BERMEJO, J. L.; CHEN, B.; WAPPENSCHMIDT, B.; MEINDL,: "Association of genetic variants in the Rho guanine nucleotide exchange factor AKAP13 with familial breast cancer", CARCINOGENESIS, vol. 27, 2006, pages 593 - 598

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107537332A (zh) * 2016-06-29 2018-01-05 丰田自动车株式会社 电极用湿润造粒体的制造装置和制造方法
WO2019060260A1 (fr) * 2017-09-19 2019-03-28 Indiana University Research And Technology Corporation Composés inhibiteurs de xpa et leur utilisation
US11207296B2 (en) 2017-09-19 2021-12-28 Indiana University Research And Technology Corporation XPA inhibitor compounds and their use
US12486246B2 (en) 2019-12-10 2025-12-02 The Trustees Of Indiana University Replication protein A (RPA)-DNA interaction inhibitors
EP4516790A1 (fr) * 2023-08-28 2025-03-05 The University Of Hong Kong Ciblage covalent de rhoa pour cancérothérapie
CN118878449A (zh) * 2024-07-23 2024-11-01 广东省中医院（广州中医药大学第二附属医院、广州中医药大学第二临床医学院、广东省中医药科学院） DC-Rhoin类似物及其制备方法和应用

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