Treating Cancer by Spindle Assembly Checkpoint Abrogation: Discovery of Two Clinical Candidates, BAY 1161909 and BAY 1217389, Targeting MPS1 Kinase.
J Med Chem
; 63(15): 8025-8042, 2020 08 13.
Article
en En
| MEDLINE
| ID: mdl-32338514
ABSTRACT
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.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Proteínas Tirosina Quinasas
/
Sistemas de Liberación de Medicamentos
/
Proteínas Serina-Treonina Quinasas
/
Proteínas de Ciclo Celular
/
Descubrimiento de Drogas
/
Puntos de Control de la Fase M del Ciclo Celular
/
Huso Acromático
/
Antineoplásicos
Límite:
Animals
/
Female
/
Humans
/
Male
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2020
Tipo del documento:
Article
País de afiliación:
Alemania