Discovery of Quinazoline-2,4(1H,3H)-dione Derivatives Containing 3-Substituted Piperizines as Potent PARP-1/2 InhibitorsâDesign, Synthesis, In Vivo Antitumor Activity, and X-ray Crystal Structure Analysis.
J Med Chem
; 64(22): 16711-16730, 2021 11 25.
Article
en En
| MEDLINE
| ID: mdl-34748333
ABSTRACT
Inhibiting PARP-1/2 offered an important arsenal for cancer treatments via interfering with DNA repair of cancer cells. Novel PARP-1/2 inhibitors were designed by capitalizing on methyl- or ethyl-substituted piperizine ring to capture the characteristics of adenine-ribose binding site (AD site), and their unique binding features were revealed by the cocrystal structures of compounds 4 and 6 in PARP-1. The investigation on structure-activity relationship resulted in compounds 24 and 32 with high enzymatic potency, binding selectivity, and significantly longer residence time for PARP-1 over PARP-2 (compound 24, PARP-1 IC50 = 0.51 nM, PARP-2 IC50 = 23.11 nM; compound 32, PARP-1 IC50 = 1.31 nM, PARP-2 IC50 = 15.63 nM). Furthermore, compound 24 was determined to be an attractive candidate molecule, which possessed an acceptable pharmacokinetic profile and produced remarkable antitumor activity in both breast cancer xenograft model and glioblastoma orthotopic model in mice, either alone or in combination treatment.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Piperazinas
/
Quinazolinas
/
Descubrimiento de Drogas
/
Inhibidores de Poli(ADP-Ribosa) Polimerasas
/
Poli(ADP-Ribosa) Polimerasa-1
/
Antineoplásicos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2021
Tipo del documento:
Article
País de afiliación:
China