WO2017021177A1 - Associations pharmaceutiques permettant une utilisation dans le traitement du cancer - Google Patents

Associations pharmaceutiques permettant une utilisation dans le traitement du cancer Download PDF

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WO2017021177A1
WO2017021177A1 PCT/EP2016/067524 EP2016067524W WO2017021177A1 WO 2017021177 A1 WO2017021177 A1 WO 2017021177A1 EP 2016067524 W EP2016067524 W EP 2016067524W WO 2017021177 A1 WO2017021177 A1 WO 2017021177A1
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cancer
combination
cells
inhibitor
bptes
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Míriam Neus TARRADO CASTELLARNAU
Marta Cascante Serratosa
Pedro Ramón DE ATAURI CARULLA
Silvia MARÍN MARTÍNEZ
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Universitat De Barcelona
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/42—Oxazoles
    • 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
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • 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
    • A61K31/655—Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
    • 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 invention relates to the field of human therapy, particularly of cancer treatment.
  • CDK4 and CDK6 are promising targets for inhibiting cell cycle progression since their overexpression is implicated in a wide range of human cancers but little is known of the metabolic consequences associated to this deregulation.
  • the deregulation of the cell cycle regulatory network through CDK4/6 inhibition should produce a large list of vulnerabilities associated to metabolic and gene expression modifications.
  • CDK 4/6 inhibitors such as palbociclib (PD0332991 ), LEE01 1 and LY2835219 are currently under clinical trials (S. Diaz-Moralli et al. "Targeting cell cycle regulation in cancer therapy", Pharmacol. Ther. 2013, vol.
  • PD0332991 has been extensively studied for its efficacy in tissue culture model systems as well as in mouse xenograft models of colorectal cancer among others (S. J. Baker et al., "CDK4: A key player in the cell cycle, development, and cancer", Genes Cancer 2012, vol. 3, pp. 658- 669). However, the efficacy profile of PD0332991 has been somewhat disappointing.
  • Glutaminase is the first essential enzyme for mitochondrial glutamine metabolism and catalyses the conversion of glutamine to glutamate, an amino acid required by cells for several crucial functions. Most cancer cells need glutamine to thrive while non-tumor cells do not show this pronounced dependence on glutamine. The dependence on glutamine metabolism probably results from an alternate use of the tricarboxylic acid (TCA) cycle to generate energy and building blocks in tumor cells, requiring a higher supply of glutamate into the TCA cycle through oketoglutarate (a-KG) to replenish the TCA cycle
  • TCA tricarboxylic acid
  • An aspect of the present invention relates to a pharmaceutical combination comprising a therapeutically effective amount of a CDK 4/6 inhibitor or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a glutaminase inhibitor or a pharmaceutically acceptable salt thereof.
  • the term "combination" as used herein refers to the combined administration of the CDK 4/6 inhibitor and the glutaminase inhibitor, which may be administered together in the same composition (i.e. through a single
  • compositions i.e. through separate
  • CDK 4/6 inhibitor refers to a dual cyclin-dependent kinase inhibitor of cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6), which inhibits the CDK4 and the CDK6.
  • the CDK 4/6 inhibitor is 6- acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1 -yl)pyridin-2-yl)amino)pyrido[2,3- d]pyrimidin-7(8H)-one hydrochloride (PD-0332991 ), 7-cyclopentyl-N,N-dimethyl-2-((5- (piperazin-1 -yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (LEE01 1 ), N,1 ,4,4-tetramethyl-8-((4-(4-methylpiperazin-1 -yl)phenyl)amino)-4,5-dihydro-1 H- pyrazolo[4,3-h]quinazoline-3-carboxamide (PHA848125), N-(5-((4-ethylpiperaz
  • the glutaminase inhibitor is 0-(2- diazoacetyl)-L-serine (azaserine), 6-diazo-5-oxo-L-norleucine (DON), glutamine, ibotenic acid, L-[aS,5S]-a-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (acivicin), bis-2-(5- phenylacetamido- 1 ,2,4- thiadiazol-2-yl)ethyl sulfide (BPTES), or 2-(pyridin-2-yl)-N-(5-(4- (6-(2-(3-(trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-1 ,3,4-thiadiazol-2- yl)acetamide (CB-839).
  • the CDK 4/6 inhibitor is 6-acetyl-8-cyclopentyl-5-methyl-2-((5- (piperazin-1 -yl)pyridin-2-yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one hydrochloride (PD- 0332991 ), and its combinations with the above-mentioned glutaminase inhibitors are particular embodiments of the invention.
  • the glutaminase inhibitor is bis-2-(5-phenylacetamido-1 ,2,4- thiadiazol-2-yl)ethyl sulfide (BPTES), and its combinations with the above-mentioned CDK 4/6 inhibitors are particular embodiments of the invention.
  • BPTES bis-2-(5-phenylacetamido-1 ,2,4- thiadiazol-2-yl)ethyl sulfide
  • the glutaminase inhibitor is 2-(pyridin-2-yl)-N-(5-(4-(6-(2-(3- (trifluoromethoxy)phenyl)acetamido)pyridazin-3-yl)butyl)-1 ,3,4-thiadiazol-2-yl)acetamide (CB-839), and its combinations with the above mentioned CDK 4/6 inhibitors are particular embodiments of the invention.
  • the molar ratio of CDK 4/6 inhibitor to glutaminase inhibitor is from 10:1 to 1 :10; preferably of 1 :4.
  • Other aspect of the present invention relates to pharmaceutical compositions comprising therapeutically effective amounts of any of the above-mentioned combinations, plus pharmaceutically acceptable excipients or carriers.
  • compositions for use as active pharmaceutical ingredients are for use in the treatment of cancer in mammals, including humans.
  • they are for use in colon cancer, breast cancer, melanoma, glioblastoma, osteosarcoma, cervical cancer, lymphoma, squamous cell skin cancer, or glioma.
  • colon cancer breast cancer, melanoma, glioblastoma, osteosarcoma, cervical cancer, lymphoma, squamous cell skin cancer, or glioma.
  • the present invention relates to methods of treatment of mammals (humans included) suffering from cancer, comprising the administration of a therapeutically effective amount of any of the above-mentioned combinations.
  • the cancer is colon cancer, breast cancer, melanoma, glioblastoma, osteosarcoma, cervical cancer, lymphoma, squamous cell skin cancer, or glioma.
  • the cancer is colon cancer or breast cancer.
  • compositions of the present invention may be administered simultaneously, separately or sequentially.
  • simultaneous means that the two therapeutic products of the combination are administered concurrently under a single administration.
  • synergistic effect in the present invention means that the effect that results from using the combination of the CDK 4/6 inhibitor and the glutaminase inhibitor, is greater than the sum of the effects that result from using either the CDK 4/6 inhibitor or the glutaminase inhibitor as a monotherapy.
  • treatment it is meant eliminating, reducing or ameliorating the cause or the effects of a disease.
  • treatment includes -but is not limited to- the following: alleviation, amelioration or elimination of one or more symptoms of the disease; diminishment of the extent of the disease; stabilized (i.e. not worsening) state of disease; delay or slowing of disease progression; amelioration or palliation of the disease state; and remission of the disease (whether partial or total).
  • compositions of the invention are useful to treat diseases in which CDK 4/6 and glutaminase play a role in mammals, including human beings.
  • diseases include -but are not limited to- proliferative disorders, particularly colon cancer, breast cancer, melanoma, glioblastoma, osteosarcoma, cervical cancer, lymphoma, squamous cell skin cancer, and glioma (cf. e.g. S. Lapenna et al., Nat. Rev. Drug. Discov. 2009, vol. 8, pp. 547-566).
  • FIG. 1A Synergistic antiproliferative effect of PD0332991 and BPTES combined treatment in HCT1 16 cells.
  • HCT1 16 cells were cultured at the indicated concentrations of inhibitors for 96 h and cell proliferation was determined by Hoechst staining.
  • FIG. 1 B-4C cell viabilities were assessed by analogous procedures.
  • FIG. 1 B Synergistic antiproliferative effect of PD0332991 and CB-839 combined treatment in HCT1 16 cells.
  • HCT1 16 cells were cultured at the indicated concentrations of inhibitors for 96 h and cell proliferation was determined by Hoechst staining.
  • FIG. 2A Synergistic antiproliferative effect of PD0332991 and BPTES combined treatment in MCF7 cells. MCF7 cells were cultured at the indicated concentrations of inhibitors for 96 h and cell proliferation was determined by Hoechst staining.
  • FIG. 2B Synergistic antiproliferative effect of PD0332991 and CB-839 combined treatment in MCF7 cells.
  • FIG. 3A Synergistic antiproliferative effect of PD0332991 and BPTES combined treatment in SKBR3 cells.
  • SKBR3 cells were incubated with PD0332991 and BPTES at the indicated concentrations for 96 h and cell proliferation was determined by Hoechst staining.
  • FIG. 3B Synergistic antiproliferative effect of PD0332991 and CB-839 combined treatment in SKBR3 cells.
  • FIG. 4A Selective cytotoxicity of PD0332991 and BPTES combined treatment for cancer cells. BJ and HCT1 16 cells were treated with PD0332991 and BPTES at the indicated concentrations for 96 h and cell proliferation was determined by Hoechst staining.
  • FIG. 4B Selective cytotoxicity of PD0332991 and BPTES combined treatment for cancer cells (2). BJ and HCT1 16 cells were treated with PD0332991 and BPTES at the indicated concentrations for 96 h and cell proliferation was determined by Hoechst staining.
  • FIG. 4C Selective cytotoxicity of PD0332991 and CB-839 combined treatment for cancer cells.
  • BJ, HCT1 16, MCF7 and SKBR3 cells were treated with PD0332991 and CB-839 at the indicated concentrations for 96 h and cell proliferation was determined by Hoechst staining.
  • FIG. 5A PD0332991 and BPTES combined treatment decreased the formation of spheroids. Images of HTC1 16 spheroids after 10 days of treatment. HCT1 16 spheroids were grown and treated for 10 days with PD0332991 (2 ⁇ ), BPTES (10 ⁇ ) and the combination of the two inhibitors (PD0332991 at 2 ⁇ and BPTES at 10 ⁇ ). C, Control; CM, Complete medium without inhibitors.
  • FIG. 5B PD0332991 and BPTES combined treatment decreased the formation of spheroids. Quantification of the total spheroid volume after 10 days of treatment.
  • FIG. 5C PD0332991 and glutaminase inhibitor (BPTES or CB-839) combined treatment decreased the formation of spheroids.
  • PD03329921 with the two glutaminase inhibitors (PD0332991 at 2 ⁇ and BPTES at 10 ⁇ , or PD0332991 at 2 ⁇ and CB-839 at 10 ⁇ ).
  • C Control;
  • CM Complete medium without inhibitors.
  • CDK4/6-inhibited and control cells Statistically significant differences between CDK4/6-inhibited and control cells were indicated at p ⁇ 0,001 ( *** ), while differences between treatment (BPTES or CB-839) and the corresponding control (PD0332991 -treated cells or untreated cells in complete medium) were shown at p ⁇ 0,001 (###) for CDK4/6-inhibited cells and at p ⁇ 001 flffl) for control cells.
  • C Control
  • CM Complete medium without inhibitors
  • Sph V Spheroid volume.
  • CDK4/6-inhibited and control cells were indicated at p ⁇ 0.001 ( *** ), while differences between treatment (BPTES or CB-839) and the corresponding control (PD0332991 -treated cells or untreated cells in complete medium) were shown at p ⁇ 0.001 (###) for CDK4/6-inhibited cells and at p ⁇ 0.01 flffl) for control cells.
  • C Control; CM, Complete medium without inhibitors; Sph V, Spheroid volume.
  • Antibiotic (10 000 U mL "1 penicillin, 10 mg mL “1 streptomycin), Dulbecco's Phosphate Buffer Saline (PBS), Trypsin EDTA solution C (0.05% trypsin-0.02% EDTA) were purchased from Biological Industries (Kibbutz Beit Haemet, Israel) and Fetal Bovine Serum (FBS) from Invitrogen (Carlsbad, CA, USA).
  • Human colorectal carcinoma HCT1 16 cells (ATCC, Manassas, VA, USA) and human breast adenocarcinoma SKBR3 cells (ATCC) were cultured in Dulbecco's modified Eagle Medium (DMEM): Nutrient mixture HAM F12 (1 :1 ) with L-glutamine and 12,5 mM D- glucose.
  • DMEM Dulbecco's modified Eagle Medium
  • Human skin BJ fibroblasts ATCC were grown in DMEM with L-glutamine and 25 mM D-glucose.
  • Human breast adenocarcinoma MCF7 cells were cultured in MEM medium without phenol red (Gibco) containing 10 mM D-glucose, 2 mM L- glutamine, 1 mM pyruvate (Biological Industries), 0.01 mg mL "1 insulin and 1 % non- essential aminoacids (Biological Industries). Media were supplemented with 10% heat- inactivated FBS, penicillin (50 U mL "1 ) and streptomycin (50 ⁇ g mL "1 ). Cells were incubated at 37 °C in a humidified atmosphere with 5% C02.
  • Cell proliferation assays Cell proliferation and viability were assessed using Hoechst stain (H033342; 2'-[4-ethoxyphenyl]-5-[4-methyl-1 -piperazinyl]-2,5'-bi-1 H-benzimidazole trihydrochloride trihydrate), a cell-permeable blue fluorescent dye that stains DNA.
  • Example 1A Effect of PD0332991 and BPTES on cell viability in HCT1 16 cells (colon cancer). It has been studied the effect of the two specific inhibitors of PD0332991 and BPTES alone or in constant ratio (1 :4) combination on HCT1 16 cell viability (FIG. 1A). HCT1 16 cells were grown in 96-well plates and treated with PD0332991 and BPTES at the specified concentrations for 96 h (Table 1 ). Then, cell proliferation was assessed by Hoechst staining.
  • Table 1A Synergistic antiproliferative effect of PD0332991 and BPTES combination treatment. HCT1 16 cells were treated for 96 h at the indicated concentrations of
  • Example 1 B Effect of PD0332991 and CB-839 on cell viability in HCT1 16 cells (colon cancer). It has been studied the effect of the two specific inhibitors of PD0332991 and CB- 839 alone or in constant ratio (10:1 ) combination on HCT1 16 cell viability (FIG. 1 B).
  • HCT1 16 cells were grown in 96-well plates and treated with PD0332991 and CB-839 at the specified concentrations for 96 h (Table 1 B).
  • the combination of PD0332991 and CB- 839 treatments in a wide dose range showed a strong synergism in the antiproliferative effect with a Cl ⁇ 0.3, what suggests that PD0332991 and CB-839 co-treatment is an efficient strategy to decrease the chemotherapeutic dose required for therapy and consequently, the overall toxicity.
  • [CB-839] ( ⁇ ) Viability (%) CI Value
  • Table 1 B Synergistic antiproliferative effect of PD0332991 and CB-839 combination treatment.
  • HCT1 16 cells were treated for 96 h at the indicated concentrations of PD0332991 and CB-839 in a constant ratio (10:1 ) combination.
  • the CI results revealed a strong synergy (Cl ⁇ 0.3) in the antiproliferative effects of PD0332991 and CB-839 at each dose combination tested.
  • Example 2A Effect of PD0332991 and BPTES on cell viability in MCF7 cells (breast cancer ER positive and HER2 negative). To determine if this combination treatment obtained similar growth inhibitory results in other cancer cell lines, the effect of
  • PD0332991 and BPTES was measured alone or in constant ratio (1 :4) combination on cell viability in MCF7 cells (breast cancer ER positive and HER2 negative). MCF7 cells were seeded in 96-well plates, incubated for 96 h at the indicated concentrations of PD0332991 and BPTES (Table 2A, FIG. 2A). In agreement with the effects on HCT1 16 cells, PD0332991 and BPTES combination exhibited a strong synergism (Cl ⁇ 0.3) at low drug cones, and a synergistic antiproliferative effect (Cl ⁇ 0.7) at a higher dose range.
  • Table 2A Synergistic antiproliferative effect of PD0332991 and BPTES combined treatment in MCF7 cells.
  • MCF7 cells were treated for 96 h at the specified concentrations of PD0332991 and BPTES in a constant ratio (1 :4) combination.
  • the CI results revealed a strong synergism (Cl ⁇ 0.3) at low drug concentrations and a synergistic antiproliferative effect (CK0.7) at the high-dose range of PD0332991 and BPTES.
  • Example 2B Effect of PD0332991 and CB-839 on cell viability in MCF7 cells (breast cancer ER positive and HER2 negative). To determine if this combination treatment obtained similar growth inhibitory results in other cancer cell lines, the effect of
  • PD0332991 and CB-839 alone or in constant ratio (10:1 ) combination on cell viability in MCF7 cells was measured.
  • MCF7 cells were seeded in 96-well plates, incubated for 96 h at the indicated concentrations of PD0332991 and CB-839 (Table 2B, FIG. 2B).
  • concentrations of PD0332991 and CB-839 Table 2B, FIG. 2B.
  • PD0332991 and CB-839 combination exhibited a very strong synergism (Cl ⁇ 0.1 ).
  • Table 2B Synergistic antiproliferative effect of PD0332991 and CB-839 combined treatment in MCF7 cells.
  • MCF7 cells were treated for 96 h at the specified concentrations of PD0332991 and CB-839 in a constant ratio (10:1 ) combination.
  • the CI results revealed a very strong synergism (Cl ⁇ 0.1 ) of PD0332991 and CB-839 at each dose combination.
  • Example 3A Effect of PD0332991 and BPTES on cell viability in SKBR3 cells (breast cancer ER negative and HER2 positive).
  • the effect of PD0332991 and BPTES alone and in constant ratio (1 :4) combination on cell viability in SKBR3 cells (breast cancer ER negative and HER2 positive) was also measured.
  • SKBR3 cells were grown in 96-well plates and incubated for 96 h at the indicated concentrations of PD0332991 and BPTES (Table 3A, FIG. 3A).
  • the simultaneous treatment of PD0332991 and BPTES exhibited a strong synergistic antiproliferative effect with a Cl ⁇ 0.3 at a wide dose range.
  • Table 3A Synergistic antiproliferative effect of PD0332991 and BPTES combined treatment in SKBR3 cells. SKBR3 cells were treated for 96 h at the specified
  • Example 3B Effect of PD0332991 and CB-839 on cell viability in SKBR3 cells (breast cancer ER negative and HER2 positive).
  • the effect of PD0332991 and CB-839 alone and in constant ratio (10:1 ) combination on cell viability in SKBR3 cells (breast cancer ER negative and HER2 positive) was also measured.
  • SKBR3 cells were grown in 96-well plates and incubated for 96 h at the indicated concentrations of PD0332991 and CB-839 (Table 3B, FIG. 3B).
  • Table 3B Synergistic antiproliferative effect of PD0332991 and CB-839 combined treatment in SKBR3 cells.
  • SKBR3 cells were treated for 96 h at the specified
  • Example 4A cell viability dose-response curve of the non-tumor BJ human foreskin fibroblast cell line using the Hoechst stain system.
  • the cell viability dose- response curve of the non-tumor BJ human foreskin fibroblast cell line was determined using the Hoechst stain assay.
  • HCT1 16 and BJ cells were grown in 96-well plates and incubated for 96 h at the indicated concentrations with PD0332991 alone or with addition of 10 ⁇ BPTES (FIG. 4A) and at the indicated concentrations of the combination of PD0332991 and BPTES (FIG.
  • Example 4B cell viability dose-response curve of the non-tumor BJ human foreskin fibroblast cell line using the Hoechst stain system.
  • the cell viability dose- response curve of the non-tumor BJ human foreskin fibroblast cell line was (FIG. 4C).
  • BJ cells were grown in 96-well plates and incubated for 96 h at the indicated concentrations with PD0332991 and CB-839, and the effect on cell proliferation was determined.
  • the simultaneous incubation with PD0332991 and CB-839 at all concentrations tested had little or no effect on non-tumor BJ cells viability but greatly impaired
  • Example 5 Combination therapy validation in 3D in vitro culture system.
  • spheroids of HCT1 16, MCF7 and SKBR3 cells as an in vitro tumor model system of intermediate complexity between standard monolayer cultures and tumors in vivo.
  • the spheroid model has been increasingly recognized as a primary tool for positive selection in innovative drug development therapies since it can remarkably reflect the 3D heterogeneous microenvironments and the therapeutically relevant pathophysiological gradients of in vivo tumor (F. Hirschhaeuser et al.,
  • HCT1 16, MCF7 and SKBR3 cells were grown in ultra low attachment plates with 2 ⁇ PD0332991 , 10 ⁇ BPTES, 10 ⁇ CB-839 and the combination of the two inhibitors (PD0332991 at 2 ⁇ and BPTES at 10 ⁇ or PD0332991 at 2 ⁇ and CB-839 at 10 ⁇ ), and were scored for spheroids after 10 days.
  • Inhibition of CDK4/6 alone decreased the anchorage-independent colony-forming growth of HCT1 16, MCF7 and SKBR3 cells (FIG.

Abstract

L'invention concerne des associations d'un inhibiteur des CDK 4/6 et d'un inhibiteur de la glutaminase utilisables pour le traitement du cancer, en particulier : le cancer du côlon, le cancer du sein, le mélanome, le glioblastome, l'ostéosarcome, le cancer du col de l'utérus, le lymphome, le carcinome épidermoïde, et le gliome. Un inhibiteur préféré des CDK 4/6 est le chlorhydrate de 6-acétyl-8-cyclopentyl-5-méthyl-2-((5-(pipérazine-1-yl)pyridine-2-yl)amino)pyrido[2,3-d]pyrimidine-7(8H)-one. Les inhibiteurs préférés de la glutaminase sont le sulfure de bis-2-(5-phénylacétamido-1,2,4-thiadiazol-2-yl)éthyl et le 2-(pyridine-2-yl)-N-(5-(4-(6-(2-(3-(trifluorométhoxy)phényl)acétamido)pyridazine-3-yl)butyl)-1,3,4-thiadiazol-2-yl)acétamide. Les associations présentent un effet synergique dans le traitement de mammifères, dont l'homme. L'administration peut être simultanée, séparée ou séquentielle.
PCT/EP2016/067524 2015-08-04 2016-07-22 Associations pharmaceutiques permettant une utilisation dans le traitement du cancer WO2017021177A1 (fr)

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CN110730664A (zh) * 2017-03-10 2020-01-24 卡利泰拉生物科技公司 含谷氨酰胺酶抑制剂的组合疗法
CN110913861A (zh) * 2017-06-29 2020-03-24 G1治疗公司 G1t38的形态学形式及其制造方法
CN117003745A (zh) * 2023-07-20 2023-11-07 南京市第一医院 Gls1/hdac双靶点抑制剂及其合成方法和应用

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