WO2013044596A1 - Inhibiteur de glutaminase de type rénal et son procédé de préparation et son utilisation - Google Patents

Inhibiteur de glutaminase de type rénal et son procédé de préparation et son utilisation Download PDF

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WO2013044596A1
WO2013044596A1 PCT/CN2012/001346 CN2012001346W WO2013044596A1 WO 2013044596 A1 WO2013044596 A1 WO 2013044596A1 CN 2012001346 W CN2012001346 W CN 2012001346W WO 2013044596 A1 WO2013044596 A1 WO 2013044596A1
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王建斌
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Wang Jianbin
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/18—Ring systems of four or more rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • Renal glutaminase inhibitor preparation method and use thereof
  • the present invention relates to an inhibitor of kidney type glutaminase, a preparation method thereof, and use thereof for treating a disease associated with an increase in renal glutaminase activity.
  • BACKGROUND OF THE INVENTION The rapid growth of tumor cells requires not only energy but also the production of new cells by nucleic acids, fatty acids and proteins.
  • Glutamine the most abundant amino acid in the human body, plays a crucial role in the growth and development of tumor cells (see, DeBerardinis, RJ et al. (2008) The biology of cancer: Metabolic reprogramming fuels cell growth And proliferation. Cell Metabolism 7: 11-20 and the literature Hsu, PP and Sabatini, DM (2008) Warburg and beyard. Cell 134: 703-707). Therefore, many tumor cells are described as cells that are "addicted to glutamine” (see Wise DR and Thompson CB (2010) Glutamine addiction: a new therapeutic target in cancer. Trends in Biochemical Sciences 35: 427- 433).
  • glutaminase is located in the lining of the mitochondria in cells (see Shapiro, RA et al. (1985) The orientation of phosphate-dependent glutaminase on the inner membrane Of rat renal mitochondria. Arch Biochem Biophys 243: 1-7), which catalyzes the reaction of glutamate to glutamate, which is converted to ⁇ -ketoglutaric acid by the action of glutamate dehydrogenase. Entering the Krebs cycle as a substrate to provide metabolic intermediates for macromolecular synthesis of tumor cells (see Lu WQ et al. (2010) Cancer metabolism: is glutamine sweeter than glucose. Cancer cell 18: 199-200) .
  • Glutamine can be divided into two isoforms, the liver type glutaminase, which is expressed only in the peripheral cells of the liver after birth; the other is called the kidney type.
  • Glutamine enzyme which is abundantly expressed in various parts of the body such as kidney, brain, intestine, liver, and lymphocytes. It is important to be present in tumor cells (see Szeliga, M and Obara-Michlewska, M). (2009) Glutamine in neoplastic cells: focus on the expression and role of glutaminases. Neurochem Int 55: 71-75 ). These two sub Although they are highly similar in amino acid sequence, they are derived from different related genes (see
  • Glutamine metabolism Nutritional and clinical significance, glutamine and cancer. J Nutr 131: 2539S-2542S ). Glutamine metabolism is carried out in the mitochondria of cells, so glutamine must be transported from the cell to the cytoplasm through the cell membrane and then transported from the cytoplasm through the mitochondrial membrane into the mitochondria (see Bode, B. (2001) recent molecular Advances in mammalian glutamine transport . J.
  • the invention is a compound of the formula: or a pharmaceutically acceptable salt thereof:
  • H is selected from the group consisting of H, halogen, (C r C 6 )alkyl; preferably H, F, Cl, Br, I; more preferably H;
  • R 2 is selected from H, OH, CKd-Ce) alkyl; preferably H, OH, OCH 3 , OCH 2 CH 3 ; more preferably H;
  • R 3 is selected from the group consisting of H, halogen, (dC 6 )alkyl, OH, 0-(dC 6 )alkyl, 0-(dC 6 )alkyl-COOH, 0-(C r C 6 )alkyl-aryl , OCO-(dC 6 )alkyl, SH, S-(dC 6 )alkyl, S-(C r C 6 )alkyl-aryl, N0 2 , NH 2 , NH-(C r C 6 ) alkane , N((dC 6 )alkyl) 2 , N-id- ⁇ )alkylaryl; preferably H, F, Cl, Br, I, OH, OCH 3 , OCH 2 CH 3 , CH (CH 3 2 , C(CH 3 ) 3 , OCH 2 COOH, OCH 2 Ph, OCOCH 3 , SCH 3 , N(CH 3 ) 2 , N(CH 2 CH 3 )
  • R4 is selected from H, halo, (C r C 6) alkyl, 0- (C r C 6) alkyl, COOH, N0 2, NH 2 , NH- (dC 6) alkyl, N ((dC 6) Alkyl) 2 , preferably H, Cl, Br, I, COOH, N0 2 , N(CH 3 ) 2 ; more preferably H, Br, N0 2 ;
  • R 3 and R 4 may form an aryl or heteroaryl group together with the carbon atom or hetero atom to which they are attached, and the aryl or heteroaryl group may be an optionally substituted aryl or heteroaryl group.
  • the aryl group is preferably a phenyl group, and the heteroaryl group is preferably a dioxole;
  • R 5 is selected from H, halogen, (dC 6 )alkyl; preferably H, F, Cl, Br; more preferably H;
  • R4 and R 5 may together with the carbon atom or hetero atom they are attached aryl or heteroaryl, said aryl or heteroaryl may be optionally substituted aryl or heteroaryl group, said aryl Base is preferably benzene Base
  • R u , R 12 and R 13 are each independently selected from H, halogen,
  • R6 and R 7 may together with the carbon atom or hetero atom to which they are attached form a C 5 -C 10, saturated or unsaturated, substituted or unsubstituted cyclic group, said cyclic group
  • the carbon in the carbon may be replaced by one or more hetero atoms selected from 0, S, N; preferably, the cyclic group is a cyclopentyl group, a cyclohexyl group, a phenyl group, an oxazole, a pyrazole, a thiazole, a different Oxazole, isothiazole, triazole;
  • a pharmaceutical composition comprising a compound of the invention and one or more pharmaceutically acceptable excipients.
  • the invention provides the use of a compound or composition of the invention for the manufacture of a medicament for inhibiting renal glutaminase.
  • the invention provides the use of a compound or composition of the invention described above for the manufacture of a medicament for the treatment or prevention of a condition associated with increased renal glutaminase activity.
  • the present invention also provides a method of treating or preventing a condition associated with an increase in renal glutaminase activity, the method comprising administering to a subject in need of such treatment or prevention a therapeutically effective amount of the present invention A compound or composition of the invention.
  • Figure 1 shows the inhibition of cancer cell growth by the exemplary compounds of the invention.
  • Figure 1A non-small lung cancer cells CRL-5803 (ATCC) and breast cancer cells MDA-MB231 (ATCC) Western blot.
  • Figure 1B shows growth inhibition of non-small lung cancer cells CRL-5803.
  • Figure 1C shows growth inhibition of breast cancer cell MDA-MB231.
  • Figure 2 shows the effect of an exemplary compound of the invention on the malignant transformation activity of cancer cells.
  • Figure 2A shows the results of non-small lung cancer cells CRL-5803 and CRL-5800 (ATCC) in a saturation density assay.
  • Figure 2B shows the results of breast cancer cells MDA-MB231 and SKBR3 (ATCC) in a saturation density experiment.
  • Figure 2C shows the results of the Low serum assay.
  • Figure 2D shows the results of the Soft agar assay.
  • Figure 3 shows that the example compounds of the invention have no effect on the growth and morphology of normal cells.
  • Figure 3A shows the effect on HMEC in human normal breast epithelial cells.
  • Figure 3B shows the morphological effects on human normal mammary epithelial cells HMEC, two breast cancer cells MDA-MB231 and SKBR3.
  • Figure 4 shows the amino acid sequence of mouse kidney glutaminase.
  • Figure 5 shows that the example compounds of the invention inhibit renal glutaminase activity.
  • Fig. 5A shows a recombinant protein expressing mouse kidney-type glutaminase in Escherichia coli, and its protease activity was measured after treatment with various concentrations of the compound. 100% means that 620 moles of glutamine can be hydrolyzed per minute per mole of glutaminase.
  • Figure 5B upper panel: MDA-MB231, SKBR3 cells were transfected with kidney glutaminase siRNA, or control siRNA, and then grown under low serum (1% FBS), respectively, on days 2, 4, and 6 Results of counting by different cells; Bottom panel: Western blot results showing the expression of glutaminase in MDA-MB231, SKBR3 cells after siRNA knockdown.
  • Figure 5C shows the results of clustering of MDA-MB 231, SKBR3 cells transfected with kidney-type glutaminase siRNA, or control siRNA, and then grown in soft agar for ten days.
  • Figure 5D MDA-MB231. SKBR3 cells were grown in RPMI 1640 + 10% FBS medium, and cell counts were performed on days 2, 4, and 6 with or without glutamine. .
  • Figure 6 shows the inhibitory effect of the exemplified compounds of the present invention on tumors in xenografted mice.
  • Figure 6A shows the inhibition of MDA-MB231 cell growth.
  • Figure 6B shows the inhibition of SKBR3 cell growth.
  • Fig. 6C shows the inhibitory effect on P-493B lymphoma cells in mice.
  • Figure 7 shows the inhibitory effect of the exemplified compounds of the invention on glutaminase activity in malignant transformation of cells.
  • the left panel shows the production of HMEC, MDA-MB231 and SKBR3 cells.
  • the invention provides a compound of the formula: or a pharmaceutically acceptable salt thereof:
  • R 2 is selected from the group consisting of H, OH, OCH 3 , OCH 2 CH 3 ;
  • R 3 is selected from the group consisting of H, F, Cl, Br, I, OH, OCH 3 , OCH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , OCH 2 COOH, OCH 2 Ph, OCOCH 3 , SCH 3 , N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 ;
  • R4 is selected from the group consisting of H, Cl, Br, I, N0 2 , N(CH 3 ) 2 ;
  • R 3 and R 4 may, together with the carbon or hetero atom to which they are attached, form an optionally substituted aryl or heteroaryl;
  • R 5 is selected from the group consisting of H, Cl, Br;
  • R u , R 12 and R 13 are each independently selected from the group consisting of H, F, Cl, Br, I, OH, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , OCH 3 , OCH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , OCH 2 COOH, OCH 2 Ph, OCOCH 3 , SCH 3 , N(CH 3 ) 2 , N(CH 2 CH 3 2 ; Z is selected from C, 0, S, N, preferably C, N.
  • R 2 is selected from the group consisting of H, OH, OCH 3 , OCH 2 CH 3 ;
  • R 3 is selected from the group consisting of H, Cl, Br, OH, OCH 3 , OCH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , OCH 2 COOH, OCH 2 Ph, OCOCH 3 , SCH 3 , N ( CH 3 ) 2 , N(CH 2 CH 3 ) 2 ;
  • R4 is selected from the group consisting of H, Cl, Br, I, N0 2 , N(CH 3 ) 2 ;
  • R 3 and R 4 may, together with the carbon or hetero atom to which they are attached, form an optionally substituted phenyl or dioxolyl;
  • R 5 is selected from the group consisting of H, Cl, Br;
  • R u , R 12 and R 13 are each independently selected from the group consisting of H, F, Cl, Br, I, OH, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , OCH 3 , OCH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , OCH 2 COOH, OCH 2 Ph, OCOCH 3 , SCH 3 , N(CH 3 ) 2 , N(CH 2 CH 3 2 ; Z is selected from C, 0, S, N.
  • Ri is selected from H;
  • R 2 is selected from the group consisting of H, OCH 3 and OCH 2 CH 3 ;
  • R 3 is selected from the group consisting of Br, OH, OCH 3 , OCH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , OCH 2 Ph, OCOCH 3 , SCH 3 , N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 ;
  • R4 is selected from the group consisting of H, Cl, Br, I, N0 2 ;
  • R 3 and R 4 may, together with the carbon or hetero atom to which they are attached, form an optionally substituted phenyl or dioxolyl;
  • R 5 is selected from H
  • R u , R 12 and R 13 are each independently selected from the group consisting of H, F, Cl, Br, I, OH, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , OCH 3 , OCH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , OCH 2 COOH, OCH 2 Ph, OCOCH 3 , SCH 3 , N(CH 3 ) 2 , N(CH 2 CH 3 2 ) ;
  • Z is selected from C and N.
  • Ri is selected from H;
  • R 2 is selected from H
  • R 3 is selected from the group consisting of Br, OCH 3 , OCH 2 CH 3 . CH(CH 3 ) 2 , C(CH 3 ) 3 , SCH 3 ;
  • R4 is selected from the group consisting of H, F, Cl, Br, N0 2 ;
  • R 3 and R 4 may, together with the carbon or hetero atom to which they are attached, form an optionally substituted phenyl or dioxolyl;
  • R 5 is selected from H
  • R u , R 12 and R 13 are each independently selected from the group consisting of H, F, Cl, Br, I, OH, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , OCH 3 , OCH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , OCH 2 COOH, OCH 2 Ph, OCOCH 3 , SCH 3 , N(CH 3 ) 2 , N(CH 2 CH 3 2 ) ;
  • d- 6 alkyl refers to a linear saturated hydrocarbon group or a branched saturated hydrocarbon group having 1 to 6 carbon atoms.
  • examples of the d- 6 alkyl group include anthracenyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl groups.
  • the hydrocarbon group is linear.
  • aryl refers to aromatic rings wherein at least one of a C 6 _ 12 monocyclic hydrocarbon or bicyclic hydrocarbon ring. Examples of such groups include phenyl (ph), naphthyl and tetrahydronaphthyl.
  • heteroaryl refers to a 5-6 membered aromatic monocyclic or fused 8-10 membered aromatic ring containing from 1 to 4 impurities selected from the group consisting of oxygen, nitrogen and sulfur. atom.
  • aromatic monocyclic rings examples include thiamidine, furyl, furazanyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazole Base, isoxazolyl, thiadiazolyl, pyranyl, pyrazolyl, pyrimidinyl, yl, pyridyl, pyridyl, triazinyl, tetrazinyl and the like.
  • aromatic bicyclic rings examples include quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, pteridinyl, porphyrinyl, phthalazinyl, naphthyridinyl, anthracene.
  • aryl or heteroaryl refers to an aryl or heteroaryl group optionally substituted by: halo, OH, (dC 6 )alkyl, CKd- ⁇ ) alkyl, O-id- ⁇ ) Pit-aryl, OCO-id- ⁇ ) Pit base, SH, S-(C r C 6 )alkyl, N0 2 , Dish 2, NH-(dC 6 )alkyl, N ((C r C 6 )alkyl)2, (C 3 -C 8 )cycloalkyl, (C 3 -C 7 )heterocyclyl.
  • halogen refers to fluoro, chloro, bromo or iodo.
  • the compound of the formula 5 can be prepared as an isomeric mixture or a racemic compound, but the present invention relates to all such enantiomers or isomers, Either in optically pure form or as a mixture with other isomers. Separate enantiomers or isomers can be obtained by methods known in the art, such as optical resolution of a product or intermediate (e.g., chiral chromatographic separation (e.g., chiral HPLC)), or enantiomeric Structure synthesis method. Similarly, when a compound of the invention is present as an alternative tautomeric form (eg, a ketone/enol, amide) The present invention relates to isolated independent tautomers and to mixtures of tautomers in all ratios.
  • the invention further relates to pharmaceutically acceptable salts of the above formulae, which are well known to those skilled in the art and include the basic salts of inorganic and organic acids, or the acid salts of inorganic or organic bases.
  • the acid is, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, acetic acid R
  • Trifluoroacetic acid malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, fumaric acid, succinic acid, maleic acid, benzoic acid, and the like.
  • the base is, for example, an alkali metal or alkaline earth metal cation, an ammonium cation or the like.
  • the compound (III) of the present invention can be reacted with 2-aminonaphthalene and substituted benzoquinone to form Schiff base (II), and then the resulting Schiff base and 5,5-dimercaptocyclohexyl-1 are produced. , 3-dione reaction to prepare. Specifically, the method includes:
  • Rl, ⁇ 2, R3, R5, R6, R7, R Rl0, Rll, Rl2 and Rl3 are as defined above.
  • the alcohol solvent is, for example, an alcohol of d- 5 , preferably ethanol.
  • the benzene solvent is, for example, benzene, toluene, dinonylbenzene, triterpene benzene, chlorobenzene, bromobenzene or the like, and benzene is preferred.
  • the Schiff base formed in the above step a can be purified or directly subjected to the next reaction without purification.
  • the reaction is carried out at reflux temperature.
  • a pharmaceutical composition comprising a compound of the invention described above together with one or more pharmaceutically acceptable excipients.
  • compositions of the present invention comprise a compound of the invention and a pharmaceutically acceptable carrier, adjuvant or vehicle.
  • pharmaceutically acceptable carriers, adjuvants and vehicles which can be used in the pharmaceutical compositions of the invention are those conventionally used in the field of pharmaceutical formulations, including, but not limited to, sugars, sugar alcohols, starches, ion exchangers, aluminas.
  • the pharmaceutical compositions of the present invention further comprise one or more additional active pharmaceutical ingredients.
  • the compounds of the invention may be administered in combination with one or more additional active pharmaceutical ingredients.
  • the composition may be in the form of a single composition comprising a compound of the invention and one or more additional active pharmaceutical ingredients.
  • the composition may be in the form of a combination of two or more separate compositions, wherein the compound of the invention is contained in one composition, one or more additional active pharmaceutical ingredients are included in one or more In a separate composition.
  • the additional active pharmaceutical ingredient may, for example, be another anti-tumor drug.
  • the anti-tumor drug can be selected from: asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, L-asparaginase, cyclophosphamide, cytarabine, dacarbazine, radiation Enterin D, daunorubicin, doxorubicin, epirubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexammine, hydroxyurea, ifosfamide, irinotecan , decanoyltetrahydrofolate, lomustine, nitrogen mustard, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, guanidine Benzamidine, raloxifene, streptozotocin, tamoxifen, thioguanine, topot
  • SAHA cycloheptyl benzoate
  • the invention also provides the use of a compound or composition of the invention for the manufacture of a medicament for inhibiting renal glutaminase.
  • the invention provides the use of a compound or composition of the invention described above for the manufacture of a medicament for the treatment or prevention of a condition associated with increased renal glutaminase activity.
  • the conditions associated with increased renal glutaminase activity of the present invention are known to those skilled in the art, such as tumors, particularly lung tumors, breast tumors, lymphomas, malignant transformations, and the like.
  • the present invention provides a therapeutic or prophylactic and renal glutaminase A method of increasing the activity associated with a condition, the method comprising administering to a subject in need of such treatment or prevention a therapeutically effective amount of a compound or composition of the invention described above.
  • Example 1 Inhibition of renal glutaminase activity
  • Kidney-type glutaminase siRNA (Stealth Select RNAi Duplexes from Invitrogen, catalog numbers: GLSMSS204740 and GLSMSS204742), or non-specific oligonucleotides used as control siRNA (Invitrogen catalog number: 12935-112)
  • Breast cancer cells MDA-MB231 and SKBR3 were transfected with Lipofectamine 2000, then grown under low serum (1% FBS) conditions, and different cells were counted on days 2, 4, and 6 (Fig. 5B upper panel).
  • the expression of glutaminase in MDA-MB231, SKBR3 cells after siRNA knockdown was shown by Western blotting (Fig. 5B lower panel).
  • SKBR3 cells were transfected with kidney-type glutaminase siRNA or control siRNA, and then grown in soft agar, and the formed clusters were counted ten days later. The results showed that treatment of siRNA against glutaminase inhibited the formation of clusters of these two breast cancer cells in adherent-independent growth (Fig. 5C).
  • SKBR3 cells were grown in RPMI 1640 + 10% FBS medium supplemented with glutamine or without glutamine, and cell counts were performed on days 2, 4, and 6 respectively.
  • the results showed that when glutamine was removed from the cell culture medium of MDA-MB 231 and SKBR3, their growth under low serum conditions was greatly inhibited (Fig. 5D), further demonstrating the growth of tumor cells against glutamine. Amide dependence. It can be seen that glutamine plays an important role in the metabolism of tumor cells.
  • the recombinant protein of mouse kidney-type glutaminase (molecular weight 65864D, shown in Figure 4) was expressed in E. coli, and its enzyme activity was measured after treatment with various concentrations of compound 002. Specific steps are as follows:
  • the gene encoding mouse glutaminase was cloned into the pET 28a vector (Novagen catalog number: 69864-3) with histidine attached to the N-terminus.
  • the glutaminase protein was further purified by anion exchange column chromatography. Recombinant 1 ⁇ glutaminase in 57 ⁇ Tris-acetic acid (pH 8.6) and 0.25 ⁇ ⁇ buffer with different concentrations of compound 002— Warm the bath, the final volume is 80 ⁇ 1, and rotate for 30 minutes. Compound 002 was diluted in DMSO so that the volume added remained constant (5 ⁇ l) in the different reactions.
  • the second reaction contained 114 ⁇ Tris-HCK PH 9.4 ), 0.35 ⁇ ⁇ , 1.7 ⁇ NAD and 6.3 U/ml glutamate dehydrogenase in a final volume of 228 ⁇ l. The absorption was measured at room temperature for 45 minutes and then at 340 nm to calculate the activity of glutaminase.
  • Mitochondria were isolated from the same number of normal mammary epithelial cells HMEC (Gibco catalog number: A10565) and breast cancer cells MDA-MB231 and SKBR3. Two breast cancer cells were treated with compound 002 or not treated, and were isolated from cells in different cases. The mitochondria are assayed for the activity of glutaminase. The results showed that mitochondria isolated from MDA-MB231 and SKBR3 cells showed significantly higher activity than normal human mammary epithelial cells HMEC. When cells were treated with compound 002, glutaminase activity was strongly inhibited (Fig. 7, left panel).
  • the EGFR-mediated signaling pathway plays an important role in regulating cell growth, cell cycle progression, cell differentiation, and biological functions of apoptosis. Overactivation of EGFR can lead to a variety of human diseases, particularly cancer (see, Pavelic, K. et al. (1993) Evidence for a role of EGF receptor in the progression of human lung carcinoma. Anticancer Research 13, 1133-1137 and The literature Slamon, D. J" et al. (1989) Studies of the HER-2/neu protooncogene in human breast and ovarian cancer. Science 244: 707-712). The study found that the expression of EGFR can be used as a diagnosis of breast cancer and lung cancer. An indicator of patient survival (see Moasser, MM (2007) The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene 26, 6469-6487).
  • Non-small lung cancer cells CRL-5803 and breast cancer cells MDA-MB231 were cultured in RPMI 1640 supplemented with 10% FBS, while cells were treated with different compounds 001, 002 or 003 (each compound in culture) The final concentration was 10 ⁇ or the cells were treated with DMSO, and the cells were lysed two days later, and Western blotting was performed using antibodies against EGFR and actin. The results are shown in Fig. 1A. As can be seen from the figure, the above compounds can significantly reduce the expression level of EGFR, thereby inhibiting the signal transduction pathway of epidermal growth factor activation.
  • Example 3 Inhibition of cell growth
  • Non-small lung cancer cells CRL-5803 and breast cancer cells MDA-MB231 were cultured in RPMI 1640 medium, 10% FBS was added, and cells were treated with compound 001, 002 or 003 (the end of each compound in the culture solution) Cells were treated at a concentration of 10 ⁇ or with DMSO and cell counts were performed up to six days. As a result, as shown in Figs. 1B and 1C, the compounds inhibited the growth of CRL-5803 and MDA-MB231 cells, but 001 and 003 for cancer. The inhibition of cell growth was significantly weaker than 002. Effect of Example 4 on the malignant transformation activity of cancer cells
  • Non-small lung cancer cells CRL-5803 and CRL-5800; breast cancer cells MDA-MB 231 and SKBR3 were cultured in RPMI 1640 medium supplemented with 10% FBS, and treated with compound 002 (the end of the compound in the culture solution) The concentration was ⁇ ) or not treated, and cell counts were performed on days 2, 4, and 6, respectively, and the results are shown in Fig. 2A and Fig. 2 ⁇ .
  • Two breast cancer cells MDA-MB231 and SKBR3, were cultured in RPMI 1640 medium supplemented with 1% FBS.
  • the cells were treated with Compound 002 (the final concentration of the compound in the culture solution was ⁇ ) or left untreated, and the cells were counted on days 2, 4, and 6, respectively, and the results are shown in Fig. 2C.
  • Two breast cancer cells MDA-MB231 and SKBR3, were grown on soft agar for 14 days, treated with compound 002 or not, and then counted for all communities larger than 50 mm in diameter, plotted against the percentage of total community. As shown in Figure 2D (top). Both breast cancer cells form large colonies in soft agar, and stop growing when they are treated with compound 002, just like a single cell ( Figure 2D below).
  • the compounds of the present invention inhibited the highly aggressive lung cancer cell CRL-5803 and the breast cancer cell MDA-MB-231, and the mild lung cancer cell CRL-5800 breast cancer cell SKBR3 cells under high density conditions.
  • Growth Fig. 2A, 2B
  • Fig. 2C inhibited the growth of breast cancer cells under low serum conditions
  • Fig. 2D inhibited anchorage-independent growth of these two cells to form clusters
  • Adherent-independent growth is an important feature of malignant transformation of cells.
  • MDA-MB231 cells and SKBR3 cells were grown in RPMI 1640 + 1% FBS culture medium, and cells were treated with compound 002 (the final concentration of the compound in the culture solution was ⁇ ), or in the treatment
  • a cell-permeable analog ( ⁇ -KG) of ⁇ -ketoglutaric acid was added, and cell counts were performed on days 2, 4, and 6, respectively, and the results showed that whether it was MDA-MB231 or SKBR3 cells, compound 002 was used.
  • ⁇ -KG cell-permeable analog of ⁇ -ketoglutaric acid
  • P-493B lymphoma cells (2 x 10 7 ) were injected subcutaneously into the flank of severely immunodeficient mice SCID (National Cancer Institute) (mouse weight 120 g-125 g), and tumors grew after 12 days. 170 mm 3 , followed by treatment of the tumor with Compound 002 by intraperitoneal injection of 200 ⁇ per day, a total of 200 ⁇ g of Compound 002, for 12 days.
  • SCID National Cancer Institute

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Abstract

La présente invention concerne un composé et une composition pharmaceutique utilisés pour l'inhibition de l'activité d'une glutaminase de type rénal, et l'utilisation du composé dans le traitement, en particulier dans le traitement ou la prévention de maladies, en particulier le cancer, associées à l'augmentation de l'activité d'une glutaminase.
PCT/CN2012/001346 2011-09-30 2012-09-29 Inhibiteur de glutaminase de type rénal et son procédé de préparation et son utilisation WO2013044596A1 (fr)

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US9938267B2 (en) 2011-11-21 2018-04-10 Calithera Biosciences, Inc. Heterocyclic inhibitors of glutaminase
WO2015101957A2 (fr) 2014-01-06 2015-07-09 Rhizen Pharmaceuticals Sa Nouveaux inhibiteurs de la glutaminase
US9783533B2 (en) 2014-01-06 2017-10-10 Rhizen Pharmaceuticals Sa Glutaminase inhibitors
WO2015101958A2 (fr) 2014-01-06 2015-07-09 Rhizen Pharmaceuticals Sa Nouveaux inhibiteurs de glutaminase
US10611759B2 (en) 2014-01-06 2020-04-07 Rhizen Pharmaceuticals Sa Glutaminase inhibitors
US9687485B2 (en) 2014-06-13 2017-06-27 Calithera Biosciences, Inc. Combination therapy with glutaminase inhibitors
US10316030B2 (en) 2014-08-07 2019-06-11 Calithera Biosciences, Inc. Crystal forms of glutaminase inhibitors
US10676472B2 (en) 2014-08-07 2020-06-09 Calithera Biosciences, Inc. Crystal forms of glutaminase inhibitors
EA035354B1 (ru) * 2015-04-06 2020-06-01 Калитера Байосайенсиз, Инк. Лечение рака легких ингибиторами глутаминазы
US10441587B2 (en) 2015-04-06 2019-10-15 Calithera Biosciences, Inc. Treatment of lung cancer with inhibitors of glutaminase
WO2016164401A1 (fr) * 2015-04-06 2016-10-13 Calithera Biosciences, Inc. Traitement du cancer du poumon avec des inhibiteurs de glutaminase
US10258619B2 (en) 2015-10-05 2019-04-16 Calithera Biosciences, Inc. Combination therapy with glutaminase inhibitors and immuno-oncology agents
US10940148B2 (en) 2015-10-05 2021-03-09 Calithera Biosciences, Inc. Combination therapy with glutaminase inhibitors and immuno-oncology agents
US10278968B2 (en) 2016-08-25 2019-05-07 Calithera Biosciences, Inc. Combination therapy with glutaminase inhibitors
US10195197B2 (en) 2016-08-25 2019-02-05 Calithera Biosciences, Inc. Combination therapy with glutaminase inhibitors
US20230095021A1 (en) * 2019-03-18 2023-03-30 Alteron Therapeutics, Inc. Modulators of tdp-43

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