Discovery of 3-hydroxymethyl-azetidine derivatives as potent polymerase theta inhibitors.
Bioorg Med Chem
; 103: 117662, 2024 Apr 01.
Article
in En
| MEDLINE
| ID: mdl-38493730
ABSTRACT
Inhibition of the low fidelity DNA polymerase Theta (Polθ) is emerging as an attractive, synthetic-lethal antitumor strategy in BRCA-deficient tumors. Here we report the AI-enabled development of 3-hydroxymethyl-azetidine derivatives as a novel class of Polθ inhibitors featuring central scaffolding rings. Structure-based drug design first identified A7 as a lead compound, which was further optimized to the more potent derivative B3 and the metabolically stable deuterated compound C1. C1 exhibited significant antiproliferative properties in DNA repair-compromised cells and demonstrated favorable pharmacokinetics, showcasing that 3-hydroxymethyl-azetidine is an effective bio-isostere of pyrrolidin-3-ol and emphasizing the potential of AI in medicinal chemistry for precise molecular modifications.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Azetidines
/
Neoplasms
Limits:
Humans
Language:
En
Journal:
Bioorg Med Chem
Journal subject:
BIOQUIMICA
/
QUIMICA
Year:
2024
Type:
Article
Affiliation country:
China