RESUMO
Inhibition of monopolar spindle 1 (MPS1) kinase represents a novel approach to cancer treatment: instead of arresting the cell cycle in tumor cells, cells are driven into mitosis irrespective of DNA damage and unattached/misattached chromosomes, resulting in aneuploidy and cell death. Starting points for our optimization efforts with the goal to identify MPS1 inhibitors were two HTS hits from the distinct chemical series "triazolopyridines" and "imidazopyrazines". The major initial issue of the triazolopyridine series was the moderate potency of the HTS hits. The imidazopyrazine series displayed more than 10-fold higher potencies; however, in the early project phase, this series suffered from poor metabolic stability. Here, we outline the evolution of the two hit series to clinical candidates BAY 1161909 and BAY 1217389 and reveal how both clinical candidates bind to the ATP site of MPS1 kinase, while addressing different pockets utilizing different binding interactions, along with their synthesis and preclinical characterization in selected in vivo efficacy models.
Assuntos
Antineoplásicos/metabolismo , Proteínas de Ciclo Celular/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Descoberta de Drogas/métodos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Fuso Acromático/efeitos dos fármacos , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Linhagem Celular Tumoral , Cães , Feminino , Células HT29 , Células HeLa , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/fisiologia , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Estrutura Terciária de Proteína , Proteínas Tirosina Quinases/antagonistas & inibidores , Ratos , Ratos Wistar , Fuso Acromático/metabolismo , Resultado do TratamentoRESUMO
Selective inhibition of exclusively transcription-regulating PTEFb/CDK9 is a promising new approach in cancer therapy. Starting from lead compound BAY-958, lead optimization efforts strictly focusing on kinase selectivity, physicochemical and DMPK properties finally led to the identification of the orally available clinical candidate atuveciclib (BAYâ 1143572). Structurally characterized by an unusual benzyl sulfoximine group, BAYâ 1143572 exhibited the best overall profile inâ vitro and inâ vivo, including high efficacy and good tolerability in xenograft models in mice and rats. BAYâ 1143572 is the first potent and highly selective PTEFb/CDK9 inhibitor to enter clinical trials for the treatment of cancer.