RESUMO
We report here the discovery of a novel series of selective mTOR kinase inhibitors and the identification of CC214-2, a compound with demonstrated anti-tumor activity upon oral dosing in a PC3 prostate cancer xenograft model. A series of 4,6-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones were discovered through a core modification of our original compound series. Analogs from this series have excellent mTOR potency and maintain selectivity over the related PI3Kα lipid kinase. Compounds such as CC214-2 were found to block both mTORC1(pS6) and mTORC2(pAktS473) signaling in PC3 cancer cells, in vitro and in vivo.
Assuntos
Antineoplásicos/química , Inibidores de Proteínas Quinases/química , Pirazinas/química , Serina-Treonina Quinases TOR/antagonistas & inibidores , Administração Oral , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Masculino , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirazinas/farmacocinética , Pirazinas/uso terapêutico , Pirazinas/toxicidade , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Transplante HeterólogoRESUMO
The serine/threonine specific protein kinase B-Raf is part of the MAPK pathway and is an interesting oncology target. We have identified thieno[2,3-d]pyrimidines as a core scaffold of small molecule B-Raf inhibitors. The SAR of analogs in this series will be described.
Assuntos
Química Farmacêutica/métodos , Inibidores de Proteínas Quinases/síntese química , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/metabolismo , Pirimidinas/farmacologia , Cristalografia por Raios X/métodos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Sistema de Sinalização das MAP Quinases , Modelos Químicos , Isoformas de Proteínas , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-Atividade , Ureia/químicaRESUMO
We report here the discovery of a novel series of selective mTOR kinase inhibitors. A series of imidazo[4,5-b]pyrazin-2-ones, represented by screening hit 1, was developed into lead compounds with excellent mTOR potency and exquisite kinase selectivity. Potent compounds from this series show >1000-fold selectivity over the related PI3Kα lipid kinase. Further, compounds such as 2 achieve mTOR pathway inhibition, blocking both mTORC1 and mTORC2 signaling, in PC3 cancer cells as measured by inhibition of pS6 and pAkt (S473).
Assuntos
Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/química , Pirazinas/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Descoberta de Drogas , Humanos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
We report here the synthesis and structure-activity relationship (SAR) of a novel series of triazole containing mammalian target of rapamycin (mTOR) kinase inhibitors. SAR studies examining the potency, selectivity, and PK parameters for a series of triazole containing 4,6- or 1,7-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones resulted in the identification of triazole containing mTOR kinase inhibitors with improved PK properties. Potent compounds from this series were found to block both mTORC1(pS6) and mTORC2(pAktS473) signaling in PC-3 cancer cells, in vitro and in vivo. When assessed in efficacy models, analogs exhibited dose-dependent efficacy in tumor xenograft models. This work resulted in the selection of CC-115 for clinical development.
Assuntos
Desenho de Fármacos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/química , Pirazinas/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Triazóis/química , Triazóis/farmacologia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Simulação de Acoplamento Molecular , Conformação Proteica , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Pirazinas/metabolismo , Pirazinas/farmacocinética , Ratos , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR/química , Serina-Treonina Quinases TOR/metabolismo , Triazóis/metabolismo , Triazóis/farmacocinética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
We report here the synthesis and structure-activity relationship (SAR) of a novel series of mammalian target of rapamycin (mTOR) kinase inhibitors. A series of 4,6- or 1,7-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones were optimized for in vivo efficacy. These efforts resulted in the identification of compounds with excellent mTOR kinase inhibitory potency, with exquisite kinase selectivity over the related lipid kinase PI3K. The improved PK properties of this series allowed for exploration of in vivo efficacy and ultimately the selection of CC-223 for clinical development.
Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Inibidores de Fosfoinositídeo-3 Quinase , Neoplasias da Próstata/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Humanos , Masculino , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Pirazinas/síntese química , Ratos , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
Several analogues of ethyl 2-[(3-methyl-2,5-dioxo(3-pyrrolinyl))amino]-4-(trifluoromethyl)pyrimidine-5-carboxylate (1) were synthesized and tested as inhibitors of AP-1 and NF-kappaB mediated transcriptional activation in Jurkat T cells. From our SAR work, ethyl 2-[(3-methyl-2,5-dioxo(3-pyrrolinyl))-N-methylamino]-4-(trifluoromethyl)-pyrimidine-5-carboxylate was identified as a novel and potent inhibitor.
Assuntos
Regulação da Expressão Gênica/fisiologia , NF-kappa B/antagonistas & inibidores , Pirimidinas/farmacologia , Pirróis/farmacologia , Fator de Transcrição AP-1/antagonistas & inibidores , Humanos , Células Jurkat , NF-kappa B/fisiologia , Pirimidinas/química , Pirróis/química , Relação Estrutura-Atividade , Fator de Transcrição AP-1/fisiologiaRESUMO
Starting from a phenol screening hit (6), three series of benzopyranone selective estrogen receptor modulators (SERMs) have been designed, synthesized, and analyzed for both estrogen receptor alpha binding affinity and in vitro activity in two cell assays. The lead compound identified, SP500263 (13), was more potent than raloxifene and tamoxifen in a cell-based assay measuring inhibition of interleukin-6 release.