RESUMO
Spleen tyrosine kinase is a new promising target for drug discovery to treat human cancer and inflammatory disorders. A series of pyrazolopyrazine-3-amine and pyrazolopyrimidine-3-amine derivatives was designed and synthesized as new spleen tyrosine kinase inhibitors. The efforts yielded compound 6h with promising spleen tyrosine kinase inhibition in both enzymatic and B-lymphoma cell proliferation assays. Additionally, compound 6h dose dependently inhibited the activation of spleen tyrosine kinase signal in human B-cell lymphoma cells. Compound 6h might serve as a lead for further development of new spleen tyrosine kinase inhibitors.
Assuntos
Inibidores de Proteínas Quinases/química , Pirazinas/química , Pirazóis/química , Piridinas/química , Baço/enzimologia , Quinase Syk/antagonistas & inibidores , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/toxicidade , Estrutura Terciária de Proteína , Pirazinas/síntese química , Pirazinas/metabolismo , Pirazinas/toxicidade , Pirazóis/síntese química , Pirazóis/metabolismo , Pirazóis/toxicidade , Piridinas/síntese química , Piridinas/metabolismo , Piridinas/toxicidade , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Quinase Syk/metabolismoRESUMO
A series of N-(3-ethynyl-2,4-difluorophenyl)sulfonamides were identified as new selective Raf inhibitors. The compounds potently inhibit B-Raf(V600E) with low nanomolar IC50 values and exhibit excellent target specificity in a selectivity profiling investigation against 468 kinases. They strongly suppress proliferation of a panel of human cancer cell lines and patient-derived melanoma cells with B-Raf(V600E) mutation while being significantly less potent to the cells with B-Raf(WT). The compounds also display favorable pharmacokinetic properties with a preferred example (3s) demonstrating significant in vivo antitumor efficacy in a xenograft mouse model of B-Raf(V600E) mutated Colo205 human colorectal cancer cells, supporting it as a promising lead compound for further anticancer drug discovery.
RESUMO
Emerging drug resistance and other drawbacks limit tubulin inhibitors' therapeutic applications and developing novel tubulin inhibitors still attracts intensive efforts. We describe the discovery and structure-activity relationship study of a series of benzimidazole-2-urea derivatives as novel ß tubulin inhibitors. The representative compound 6o potently suppressed the proliferation of a panel of human cancer cells (NCI-H460, Colo205, K562, A431, HepG2, Hela, MDA-MB-435S) with IC50 values of 0.040, 0.050, 0.006, 0.026, 1.774, 0.452 and 0.052 µM, respectively. Compound 6o obviously inhibited NCI-H460 spindles formation and induced cell cycle arrest at G2/M phase at 0.10 µM. Computational study suggested that 6o interacts with ß tubulin in a novel binding mode. Our results suggested that benzimidazole-2-urea derivatives might be promising tubulin inhibitors with novel binding mode for further development.
Assuntos
Antineoplásicos/farmacologia , Benzimidazóis/farmacologia , Compostos de Metilureia/farmacologia , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Benzimidazóis/síntese química , Benzimidazóis/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Fase G2/efeitos dos fármacos , Células HeLa , Células Hep G2 , Humanos , Células K562 , Compostos de Metilureia/síntese química , Compostos de Metilureia/química , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese químicaRESUMO
Bcr-Abl(T315I) mutation-induced imatinib resistance remains a major challenge for clinical management of chronic myelogenous leukemia (CML). Herein, we report GZD824 (10a) as a novel orally bioavailable inhibitor against a broad spectrum of Bcr-Abl mutants including T315I. It tightly bound to Bcr-Abl(WT) and Bcr-Abl(T315I) with K(d) values of 0.32 and 0.71 nM, respectively, and strongly inhibited the kinase functions with nanomolar IC(50) values. The compound potently suppressed proliferation of Bcr-Abl-positive K562 and Ku812 human CML cells with IC(50) values of 0.2 and 0.13 nM, respectively. It also displayed good oral bioavailability (48.7%), a reasonable half-life (10.6 h), and promising in vivo antitumor efficacy. It induced tumor regression in mouse xenograft tumor models driven by Bcr-Abl(WT) or the mutants and significantly improved the survival of mice bearing an allograft leukemia model with Ba/F3 cells harboring Bcr-Abl(T315I). GZD824 represents a promising lead candidate for development of Bcr-Abl inhibitors to overcome acquired imatinib resistance.
Assuntos
Antineoplásicos/farmacologia , Benzamidas/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Mutação , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazóis/farmacologia , Pirimidinas/farmacologia , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Benzamidas/administração & dosagem , Benzamidas/farmacocinética , Disponibilidade Biológica , Linhagem Celular Tumoral , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Mesilato de Imatinib , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Fosforilação , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Tirosina Quinases/metabolismo , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
A series of 3-(1H-1,2,3-triazol-1-yl)benzamide derivatives were designed and synthesized as new Bcr-Abl inhibitors by using combinational strategies of bioisosteric replacement, scaffold hopping, and conformational constraint. The compounds displayed significant inhibition against a broad spectrum of Bcr-Abl mutants including the gatekeeper T315I and p-loop mutations, which are associated with disease progression in CML. The most potent compounds 6q and 6qo strongly inhibited the kinase activities of Bcr-Abl(WT) and Bcr-Abl(T315I) with IC(50) values of 0.60, 0.36 and 1.12, 0.98 nM, respectively. They also potently suppressed the proliferation of K562, KU812 human CML cells, and a panel of murine Ba/F3 cells ectopically expressing either Bcr-Abl(WT) or any of a panel of other Bcr-Abl mutants that have been shown to contribute to clinical acquired resistance, including Bcr-Abl(T315I), with IC(50) values in low nanomolar ranges. These compounds may serve as lead compounds for further development of new Bcr-Abl inhibitors capable of overcoming clinical acquired resistance against imatinib.