RESUMO
Anaplastic lymphoma kinase (ALK) receptor tyrosine kinase is considered an attractive therapeutic target for human cancers, especially non-small cell lung cancer (NSCLC). Our previous study revealed that 8,9-side-chains of 6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole scaffold crucially affected kinase selectivity, cellular activity, and metabolic stability. In this work, we optimized the side-chains and identified highly selective, orally active and potent ALK inhibitor CH5424802 (18a) as the clinical candidate.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Administração Oral , Quinase do Linfoma Anaplásico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Haplorrinos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Ratos , Ratos Sprague-Dawley , Receptores Proteína Tirosina Quinases/metabolismoRESUMO
Proliferation of endothelial cells is critical for angiogenesis. We report orally available, in vivo active antiangiogenic agents which specifically inhibit endothelial cell proliferation. After identifying human umbilical vein endothelial cell (HUVEC) proliferation inhibitors from a cell-based high-throughput screening (HTS), we eliminated those compounds which showed cytotoxicity against HCT116 and vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitory activity. Evaluations in human Calu-6 xenograft model delivered lead compound 1. Following extensive lead optimization and alteration of the scaffold we discovered 32f and 32g, which both inhibited the proliferation and tube formation of HUVEC without showing inhibitory activity against any of 25 kinases or cytotoxicity against either normal fibroblasts or 40 cancer cell lines. Upon oral administration, 32f and 32g had good pharmacokinetic profiles and potent antitumor activity and decreased microvessel density (MVD) in Calu-6 xenograft model. Combination therapy with a VEGFR inhibitor enhanced the in vivo efficacy. These results suggest that 32f and 32g may have potential for use in cancer treatment.
Assuntos
Inibidores da Angiogênese , Compostos de Benzil/química , Células Endoteliais/efeitos dos fármacos , Éteres Fenílicos/química , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Benzamidas/síntese química , Benzamidas/farmacologia , Compostos de Benzil/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Éteres Fenílicos/farmacologia , Relação Estrutura-Atividade , Estirenos/síntese química , Estirenos/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Anaplastic lymphoma kinase (ALK) receptor tyrosine kinase is considered a promising therapeutic target for human cancers. We identified novel tetracyclic derivatives as potent ALK inhibitors. Among them, compound 27 showed strong cytotoxicity against KARPAS-299 with an IC(50) value of 21 nM and significant antitumor efficacy in ALK fusion-positive blood and solid cancer xenograft models in mice without body weight loss.
Assuntos
Antineoplásicos/síntese química , Descoberta de Drogas , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Tetraciclinas/síntese química , Quinase do Linfoma Anaplásico , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Tetraciclinas/química , Tetraciclinas/farmacologiaRESUMO
The MAP kinase pathway is one of the most important pathways involved in cell proliferation and differentiation, and its components are promising targets for antitumor drugs. Design and synthesis of a novel MEK inhibitor, based on the 3D-structural information of the target enzyme, and then multidimensional optimization including metabolic stability, physicochemical properties and safety profiles were effectively performed and led to the identification of a clinical candidate for an orally available potent MEK inhibitor, CH4987655, possessing a unique 3-oxo-oxazinane ring structure at the 5-position of the benzamide core structure. CH4987655 exhibits slow dissociation from the MEK enzyme, remarkable in vivo antitumor efficacy both in mono- and combination therapy, desirable metabolic stability, and insignificant MEK inhibition in mouse brain, implying few CNS-related side effects in human. An excellent PK profile and clear target inhibition in PBMC were demonstrated in a healthy volunteer clinical study.
Assuntos
Antineoplásicos/química , Benzamidas/química , MAP Quinase Quinase Quinases/antagonistas & inibidores , Oxazinas/química , Inibidores de Proteínas Quinases/química , Administração Oral , Regulação Alostérica , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Benzamidas/administração & dosagem , Benzamidas/farmacologia , Humanos , Modelos Moleculares , Oxazinas/administração & dosagem , Oxazinas/farmacologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacologiaRESUMO
A series of benzofuran-based farnesyltransferase inhibitors have been designed and synthesized as antitumor agents. Among them, 11f showed the most potent enzyme inhibitory activity (IC(50)=1.1nM) and antitumor activity in human cancer xenografts in mice.
Assuntos
Antineoplásicos/síntese química , Benzofuranos/síntese química , Química Farmacêutica/métodos , Farnesiltranstransferase/antagonistas & inibidores , Quinolonas/síntese química , Animais , Antineoplásicos/farmacologia , Benzofuranos/farmacologia , Cristalografia por Raios X , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Farnesiltranstransferase/química , Humanos , Concentração Inibidora 50 , Camundongos , Transplante de Neoplasias , Quinolonas/farmacologia , Relação Estrutura-AtividadeRESUMO
9-Substituted 6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazoles were discovered as highly selective and potent anaplastic lymphoma kinase (ALK) inhibitors by structure-based drug design. The high target selectivity was achieved by introducing a substituent close to the E(0) region of the ATP binding site, which has a unique amino acid sequence. Among the identified inhibitors, compound 13d showed highly selective and potent inhibitory activity against ALK with an IC(50) value of 2.9 nM and strong antiproliferative activity against KARPAS-299 with an IC(50) value of 12.8 nM. The compound also displayed significant antitumor efficacy in an established ALK fusion gene-positive anaplastic large-cell lymphoma (ALCL) xenograft model in mice without body weight loss.