2. Academic Validation
  3. Discovery of 3-hydroxymethyl-azetidine derivatives as potent polymerase theta inhibitors

Discovery of 3-hydroxymethyl-azetidine derivatives as potent polymerase theta inhibitors

  • Bioorg Med Chem. 2024 Apr 1:103:117662. doi: 10.1016/j.bmc.2024.117662.
Yazhou Wang 1,  Chao Wang 1,  Jinxin Liu 1,  Deheng Sun 1,  Fanye Meng 1,  Man Zhang 1,  Alex Aliper 2,  Feng Ren 1,  Alex Zhavoronkov 3,  Xiao Ding 4
Affiliations

Affiliations

  • 1 Insilico Medicine Shanghai Ltd, Suite 901, Tower C, Changtai Plaza, 2889 Jinke Road, Pudong New District, Shanghai 201203, China.
  • 2 Insilico Medicine AI Limited, Masdar City, Abu Dhabi 145748, United Arab Emirates.
  • 3 Insilico Medicine Shanghai Ltd, Suite 901, Tower C, Changtai Plaza, 2889 Jinke Road, Pudong New District, Shanghai 201203, China; Insilico Medicine AI Limited, Masdar City, Abu Dhabi 145748, United Arab Emirates.
  • 4 Insilico Medicine Shanghai Ltd, Suite 901, Tower C, Changtai Plaza, 2889 Jinke Road, Pudong New District, Shanghai 201203, China. Electronic address: xiao.ding@insilico.ai.
PMID: 38493730 DOI: 10.1016/j.bmc.2024.117662
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.

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