RESUMO
While the discovery of immune checkpoint inhibitors has led to robust, durable responses in a range of cancers, many patients do not respond to currently available therapeutics. Therefore, an urgent need exists to identify alternative mechanisms to augment the immune-mediated clearance of tumors. Hematopoetic progenitor kinase 1 (HPK1) is a serine-threonine kinase that acts as a negative regulator of T-cell receptor (TCR) signaling, to dampen the immune response. Herein we describe the structure-based discovery of isofuranones as inhibitors of HPK1. Optimization of the chemotype led to improvements in potency, selectivity, plasma protein binding, and metabolic stability, culminating in the identification of compound 24. Oral administration of 24, in combination with an anti-PD1 antibody, demonstrated robust enhancement of anti-PD1 efficacy in a syngeneic tumor model of colorectal cancer.
RESUMO
Pyrrolidine, pyrrolidinone, carbocyclic, and acyclic groups were used as isosteric proline replacements in a series of insulin-like growth factor I receptor kinase/insulin receptor kinase inhibitors. Examples that were similar in potency to proline-containing reference compounds were shown to project a key fluoropyridine amide into a common space, while less potent compounds were not able to do so for reasons of stereochemistry or structural rigidity.
Assuntos
Prolina/química , Inibidores de Proteínas Quinases/química , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor de Insulina/antagonistas & inibidores , Triazinas/química , Modelos Moleculares , Inibidores de Proteínas Quinases/farmacologia , Triazinas/farmacologiaRESUMO
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.
Assuntos
Benzimidazóis/química , Piperazinas/química , Inibidores de Proteínas Quinases/química , Piridonas/química , Administração Oral , Animais , Benzimidazóis/síntese química , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A , Humanos , Camundongos , Camundongos Nus , Piperazinas/síntese química , Piperazinas/farmacocinética , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Piridonas/síntese química , Piridonas/farmacocinética , Piridonas/farmacologia , Ratos , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/metabolismo , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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.
Assuntos
Antineoplásicos/química , Benzimidazóis/química , Inibidores de Proteínas Quinases/química , Receptor IGF Tipo 1/antagonistas & inibidores , Receptores de Esteroides/genética , Ativação Transcricional , Administração Oral , Animais , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Benzimidazóis/síntese química , Benzimidazóis/farmacocinética , Linhagem Celular Tumoral , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Humanos , Camundongos , Camundongos Nus , Receptor de Pregnano X , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Receptor IGF Tipo 1/metabolismo , Receptores de Esteroides/metabolismo , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
This report describes the biological activity, characterization, and SAR leading to 9d (BMS-754807) a small molecule IGF-1R kinase inhibitor in clinical development.
Assuntos
Pesquisa Biomédica , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Triazinas/farmacologia , Animais , Cães , Descoberta de Drogas , Humanos , Camundongos , Modelos Moleculares , Conformação Molecular , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/química , Pirazóis/farmacocinética , Pirazóis/uso terapêutico , Ratos , Receptor IGF Tipo 1/química , Relação Estrutura-Atividade , Triazinas/química , Triazinas/farmacocinética , Triazinas/uso terapêuticoRESUMO
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.
Assuntos
Benzimidazóis/farmacologia , Inibidores do Citocromo P-450 CYP3A , Receptor IGF Tipo 1/antagonistas & inibidores , Trifosfato de Adenosina/química , Administração Oral , Área Sob a Curva , Química Farmacêutica/métodos , Citocromo P-450 CYP3A/química , Desenho de Fármacos , Flúor/química , Humanos , Concentração Inibidora 50 , Modelos Químicos , Nitrogênio/química , Receptor IGF Tipo 1/química , Somatomedinas/química , Timidina/químicaRESUMO
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.
Assuntos
Benzimidazóis/química , Benzimidazóis/farmacologia , Piridonas/química , Piridonas/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Humanos , Camundongos , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Ligação Proteica , Soro , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Inibidores das Enzimas do Citocromo P-450 , Imidazóis/química , Imidazóis/farmacologia , Receptor IGF Tipo 1/antagonistas & inibidores , Animais , Sistema Enzimático do Citocromo P-450/análise , Imidazóis/síntese química , Concentração Inibidora 50 , Relação Estrutura-AtividadeRESUMO
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.