RESUMEN
Programmed cell death protein 1 (PD-1) immune checkpoint blockade therapy has revolutionized cancer treatment. Although PD-1 blockade is effective in a subset of patients with cancer, many fail to respond because of either primary or acquired resistance. Thus, next-generation strategies are needed to expand the depth and breadth of clinical responses. Toward this end, we designed a human primary T cell phenotypic high-throughput screening strategy to identify small molecules with distinct and complementary mechanisms of action to PD-1 checkpoint blockade. Through these efforts, we selected and optimized a chemical series that showed robust potentiation of T cell activation and combinatorial activity with αPD-1 blockade. Target identification was facilitated by chemical proteomic profiling with a lipid-based photoaffinity probe, which displayed enhanced binding to diacylglycerol kinase α (DGKα) in the presence of the active compound, a phenomenon that correlated with the translocation of DGKα to the plasma membrane. We further found that optimized leads within this chemical series were potent and selective inhibitors of both DGKα and DGKζ, lipid kinases that constitute an intracellular T cell checkpoint that blunts T cell signaling through diacylglycerol metabolism. We show that dual DGKα/ζ inhibition amplified suboptimal T cell receptor signaling mediated by low-affinity antigen presentation and low major histocompatibility complex class I expression on tumor cells, both hallmarks of resistance to PD-1 blockade. In addition, DGKα/ζ inhibitors combined with αPD-1 therapy to elicit robust tumor regression in syngeneic mouse tumor models. Together, these findings support targeting DGKα/ζ as a next-generation T cell immune checkpoint strategy.
Asunto(s)
Neoplasias , Receptor de Muerte Celular Programada 1 , Ratones , Animales , Humanos , Receptor de Muerte Celular Programada 1/metabolismo , Proteómica , Diacilglicerol Quinasa/metabolismo , Linfocitos T , LípidosRESUMEN
We report herein, the discovery of BMS-737 (compound 33) as a potent, non-steroidal, reversible small molecule inhibitor demonstrating 11-fold selectivity for CYP17 lyase over CYP17 hydroxylase, as well as a clean xenobiotic CYP profile for the treatment of castration-resistant prostate cancer (CRPC). Extensive SAR studies on the initial lead 1 at three different regions of the molecule resulted in the identification of BMS-737, which demonstrated a robust 83% lowering of testosterone without any significant perturbation of the mineralocorticoid and glucocorticoid levels in cynomologous monkeys in a 1-day PK/PD study.
Asunto(s)
Liasas , Neoplasias de la Próstata Resistentes a la Castración , Neoplasias de la Próstata , Antagonistas de Andrógenos , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Glucocorticoides , Humanos , Masculino , Mineralocorticoides , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Esteroide 17-alfa-Hidroxilasa , Testosterona , XenobióticosRESUMEN
Novel imidazole-based TGFßR1 inhibitors were identified and optimized for potency, selectivity, and pharmacokinetic and physicochemical characteristics. Herein, we report the discovery, optimization, and evaluation of a potent, selective, and orally bioavailable TGFßR1 inhibitor, 10 (BMS-986260). This compound demonstrated functional activity in multiple TGFß-dependent cellular assays, excellent kinome selectivity, favorable pharmacokinetic properties, and curative in vivo efficacy in combination with anti-PD-1 antibody in murine colorectal cancer (CRC) models. Since daily dosing of TGFßR1 inhibitors is known to cause class-based cardiovascular (CV) toxicities in preclinical species, a dosing holiday schedule in the anti-PD-1 combination efficacy studies was explored. An intermittent dosing regimen of 3 days on and 4 days off allowed mitigation of CV toxicities in one month dog and rat toxicology studies and also provided similar efficacy as once daily dosing.
RESUMEN
A series of 3-[6-(4-substituted-piperazin-1-yl)-4-methyl-1H-benzimidazol-2-yl]-1H-pyridine-2-one were synthesized to modulate CYP3A4 inhibition and improve aqueous solubility of our prototypical compound BMS-536924 (1), while maintaining potent IGF-1R inhibitory activity. Structure-activity and structure-solubility studies led to the identification of BMS-577098 (27), which demonstrates oral in vivo efficacy in animal models. The improvement was achieved by replacing morpholine with more polar bio-isoster piperazine and modulating the basicity of distal nitrogen with appropriate substitutions.
Asunto(s)
Bencimidazoles/química , Piperazinas/química , Inhibidores de Proteínas Quinasas/química , Piridonas/química , Administración Oral , Animales , Bencimidazoles/síntesis química , Bencimidazoles/farmacocinética , Bencimidazoles/farmacología , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A , Humanos , Ratones , Ratones Desnudos , Piperazinas/síntesis química , Piperazinas/farmacocinética , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Piridonas/síntesis química , Piridonas/farmacocinética , Piridonas/farmacología , Ratas , Receptor IGF Tipo 1/antagonistas & inhibidores , Receptor IGF Tipo 1/metabolismo , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The SAR of PXR transactivation by 3-(benzimidazol-2-yl)-pyridine-2-one based ATP competitive inhibitors of Insulin-like Growth Factor 1 Receptor kinase (IGF-1R) is discussed. Compounds without PXR transactivation, with in vivo antitumor activity, reduced protein binding and improved oral exposure are presented.
Asunto(s)
Antineoplásicos/química , Bencimidazoles/química , Inhibidores de Proteínas Quinasas/química , Receptor IGF Tipo 1/antagonistas & inhibidores , Receptores de Esteroides/genética , Activación Transcripcional , Administración Oral , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Bencimidazoles/síntesis química , Bencimidazoles/farmacocinética , Línea Celular Tumoral , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Humanos , Ratones , Ratones Desnudos , Receptor X de Pregnano , Unión Proteica , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Receptor IGF Tipo 1/metabolismo , Receptores de Esteroides/metabolismo , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
This report describes the biological activity, characterization, and SAR leading to 9d (BMS-754807) a small molecule IGF-1R kinase inhibitor in clinical development.
Asunto(s)
Investigación Biomédica , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Receptor IGF Tipo 1/antagonistas & inhibidores , Triazinas/farmacología , Animales , Perros , Descubrimiento de Drogas , Humanos , Ratones , Modelos Moleculares , Conformación Molecular , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/química , Pirazoles/farmacocinética , Pirazoles/uso terapéutico , Ratas , Receptor IGF Tipo 1/química , Relación Estructura-Actividad , Triazinas/química , Triazinas/farmacocinética , Triazinas/uso terapéuticoRESUMEN
We previously reported that 1 (BMS-536924), a benzimidazole inhibitor of the insulin-like growth factor-1 receptor, had demonstrated in vivo antitumor activity. This lead compound was found to have potent CYP3A4 inhibition, CYP3A4 induction mediated by PXR transactivation, poor aqueous solubility, and high plasma protein binding. Herein we disclose the evolution of this chemotype to address these issues. This effort led to 10 (BMS-695735), which exhibits improved ADME properties, a low risk for drug-drug interactions, and in vivo efficacy in multiple xenograft models.
Asunto(s)
Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Bencimidazoles/administración & dosificación , Bencimidazoles/farmacología , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacología , Piridonas/administración & dosificación , Piridonas/farmacología , Receptor IGF Tipo 1/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/química , Bencimidazoles/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Citocromo P-450 CYP3A , Inhibidores del Citocromo P-450 CYP3A , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Ratones Desnudos , Estructura Molecular , Trasplante de Neoplasias , Receptor X de Pregnano , Inhibidores de Proteínas Quinasas/química , Piridonas/química , Receptores de Esteroides/efectos de los fármacos , Receptores de Esteroides/metabolismo , Solubilidad , Estereoisomerismo , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
3-(Benzimidazol-2-yl)-pyridine-2-one-based ATP competitive inhibitors of Insulin-like Growth Factor 1 Kinase (IGF-IR) were optimized for reduced Cyp3A4 inhibition and improved oral exposure. The use of malonate as methyl anion synthon via S(N)Ar reaction and double decarboxylation under mild conditions is demonstrated.
Asunto(s)
Bencimidazoles/farmacología , Inhibidores del Citocromo P-450 CYP3A , Receptor IGF Tipo 1/antagonistas & inhibidores , Adenosina Trifosfato/química , Administración Oral , Área Bajo la Curva , Química Farmacéutica/métodos , Citocromo P-450 CYP3A/química , Diseño de Fármacos , Flúor/química , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Nitrógeno/química , Receptor IGF Tipo 1/química , Somatomedinas/química , Timidina/químicaRESUMEN
A series of IGF-1R inhibitors is disclosed, wherein the (m-chlorophenyl)ethanol side chain of BMS-536924 (1) is replaced with a series of 2-(1H-imidazol-4-yl)ethanamine and 2-(1H-pyrazol-1-yl)ethanamine side chains. Some analogs show improved IGF-1R potency and oral exposure. Analogs from both series, 16a and 17f, show in vivo activity comparable to 1 in our constitutively activated IGF-1R Sal tumor model. This may be the due to the improved protein binding in human and mouse serum for imidazole 16a and the excellent oral exposure of pyrazole 17f.
Asunto(s)
Bencimidazoles/química , Bencimidazoles/farmacología , Piridonas/química , Piridonas/farmacología , Receptor IGF Tipo 1/antagonistas & inhibidores , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Humanos , Ratones , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Unión Proteica , Suero , Relación Estructura-ActividadRESUMEN
A series of 3-(1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one inhibitors of insulin-like growth factor receptor-1 (IGF-1R) were examined in which the pendant imidazole moiety was replaced to improve selectivity for IGF-1R inhibition over cytochrome P450 (CYP). Synthesis and SAR of these compounds is presented.
Asunto(s)
Inhibidores Enzimáticos del Citocromo P-450 , Imidazoles/química , Imidazoles/farmacología , Receptor IGF Tipo 1/antagonistas & inhibidores , Animales , Sistema Enzimático del Citocromo P-450/análisis , Imidazoles/síntesis química , Concentración 50 Inhibidora , Relación Estructura-ActividadRESUMEN
The discovery and synthesis of 3-(1H-benzo[d]imidazol-2-yl)pyridin-2(1H)-one inhibitors of insulin-like growth factor 1-receptor (IGF-1R) are presented. Installing amine containing side chains at the 4-position of pyridone ring significantly improved the enzyme potency. SAR and biological activity of these compounds is presented.
Asunto(s)
Piridinas/síntesis química , Piridinas/farmacología , Receptor IGF Tipo 1/antagonistas & inhibidores , Bencimidazoles , Línea Celular , Humanos , Concentración 50 Inhibidora , Piridonas , Relación Estructura-ActividadRESUMEN
A novel class of 1H-(benzimidazol-2-yl)-1H-pyridin-2-one inhibitors of insulin-like growth factor I (IGF-1R) kinase is described. This report discusses the SAR of 4-(2-hydroxy-2-phenylethylamino)-substituted pyridones with improved IGF-1R potency.
Asunto(s)
Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Factor I del Crecimiento Similar a la Insulina/antagonistas & inhibidores , Fosfotransferasas/antagonistas & inhibidores , Animales , Baculoviridae/enzimología , Línea Celular , Proliferación Celular/efectos de los fármacos , Indicadores y Reactivos , Ratones , Modelos Moleculares , Piridonas/farmacología , Relación Estructura-Actividad , Timidina/metabolismoRESUMEN
Compound 3 (BMS-536924), a novel small-molecule inhibitor of the insulin-like growth factor receptor kinase with equal potency against the insulin receptor is described. The in vitro and in vivo biological activity of this interesting compound is also reported.
Asunto(s)
Antineoplásicos/síntesis química , Bencimidazoles/síntesis química , Piridinas/síntesis química , Piridonas/síntesis química , Receptor IGF Tipo 1/antagonistas & inhibidores , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Bencimidazoles/química , Bencimidazoles/farmacología , Disponibilidad Biológica , Línea Celular Tumoral , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Haplorrinos , Humanos , Ratones , Ratones Desnudos , Modelos Moleculares , Estructura Molecular , Trasplante de Neoplasias , Piridinas/química , Piridinas/farmacología , Piridonas/química , Piridonas/farmacología , Ratas , Receptor de Insulina/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
The insulin-like growth factor I receptor (IGF-IR) is a transmembrane tyrosine kinase that is essential to growth and development and also thought to provide a survival signal for the maintenance of the transformed phenotype. There has been increasing interest in further understanding the role of IGF-I signaling in cancer and in developing receptor antagonists for therapeutic application. We describe herein a novel animal model that involves transgenic expression of a fusion receptor that is constitutively activated by homodimerization. Transgenic mice that expressed the activated receptor showed aberrant development of the mammary glands and developed salivary and mammary adenocarcinomas as early as 8 weeks of age. Xenograft tumors and a cell line were derived from the transgenic animals and are sensitive to inhibition by a novel small-molecule inhibitor of the IGF-IR kinase. This new model should provide new opportunities for further understanding how aberrant IGF-IR signaling leads to tumorigenesis and for optimizing novel antagonists of the receptor kinase.