RESUMO
Pim kinases have been targets of interest for a number of therapeutic areas. Evidence of durable single-agent efficacy in human clinical trials validated Pim kinase inhibition as a promising therapeutic approach for multiple myeloma patients. Here, we report the compound optimization leading to GDC-0339 (16), a potent, orally bioavailable, and well tolerated pan-Pim kinase inhibitor that proved efficacious in RPMI8226 and MM.1S human multiple myeloma xenograft mouse models and has been evaluated as an early development candidate.
Assuntos
Antineoplásicos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Pirazóis/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Cães , Feminino , Humanos , Macaca fascicularis , Células Madin Darby de Rim Canino , Masculino , Camundongos SCID , Estrutura Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Pirazóis/síntese química , Pirazóis/metabolismo , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Fatty acid binding protein 6 (FABP6) is a potential drug discovery target, which, if inhibited, may have a therapeutic benefit for the treatment of diabetes. Currently, there are no published inhibitors of FABP6, and with the target believed to be amenable to fragment-based drug discovery, a structurally enabled program was initiated. This program successfully identified fragment hits using the surface plasmon resonance (SPR) platform. Several hits were validated with SAR and were found to be displaced by the natural ligand taurocholate. We report the first crystal structure of human FABP6 in the unbound form, in complex with cholate, and with one of the key fragments.
Assuntos
Ácidos e Sais Biliares/química , Proteínas de Ligação a Ácido Graxo/química , Hormônios Gastrointestinais/química , Sítios de Ligação , Cristalografia por Raios X , Proteínas de Ligação a Ácido Graxo/antagonistas & inibidores , Hormônios Gastrointestinais/antagonistas & inibidores , Humanos , Modelos Moleculares , Conformação Proteica , Relação Estrutura-Atividade , Ressonância de Plasmônio de Superfície , Ácido Taurocólico/químicaRESUMO
MAPKAPK5 has been proposed to play a role in regulation of matrix metalloprotease expression and so to be a potential target for intervention in rheumatoid arthritis. We present here the identification of a series of compounds against this target which are effective in both biochemical and cell assays. The expansion of the series is described, along with early SAR and pharmacokinetics for some representative compounds.
