Design of Selective PARP-1 Inhibitors and Antitumor Studies.
J Med Chem
; 67(11): 8877-8901, 2024 Jun 13.
Article
in En
| MEDLINE
| ID: mdl-38776379
ABSTRACT
Designing selective PARP-1 inhibitors has become a new strategy for anticancer drug development. By sequence comparison of PARP-1 and PARP-2, we identified a possible selective site (S site) consisting of several different amino acid residues of α-5 helix and D-loop. Targeting this S site, 140 compounds were designed, synthesized, and characterized for their anticancer activities and mechanisms. Compound I16 showed the highest PARP-1 enzyme inhibitory activity (IC50 = 12.38 ± 1.33 nM) and optimal selectivity index over PARP-2 (SI = 155.74). Oral administration of I16 (25 mg/kg) showed high inhibition rates of Hela and SK-OV-3 tumor cell xenograft models, both of which were higher than those of the oral positive drug Olaparib (50 mg/kg). In addition, I16 has an excellent safety profile, without significant toxicity at high oral doses. These findings provide a novel design strategy and chemotype for the development of safe, efficient, and highly selective PARP-1 inhibitors.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Drug Design
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Poly(ADP-ribose) Polymerase Inhibitors
/
Poly (ADP-Ribose) Polymerase-1
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Antineoplastic Agents
Limits:
Animals
/
Female
/
Humans
Language:
En
Journal:
J Med Chem
Journal subject:
QUIMICA
Year:
2024
Document type:
Article
Affiliation country:
China
Country of publication:
Estados Unidos