Rational Design and Biological Evaluation of a Novel Polθ Polymerase Inhibitor for Synergistic Targeting of HR-Deficient Cancers

  • J Med Chem. 2025 Nov 27;68(22):23801-23824. doi: 10.1021/acs.jmedchem.5c00818.
Ziheng Yu  1 ,  Zhen Li  2 ,  Lei Jiang  2 ,  Yibin Zhang  1 ,  Jingxue Zhang  1 ,  Lu Liu  2 ,  Ying Qu  2 ,  Yuchen Wei  1 ,  Mengying Li  2 ,  Tao Lu  1 ,  Zhengtao Li  2 ,  Yadong Chen  1 ,  Jie Feng  1
Affiliations
  • 1. School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, PR China.
  • 2. State Key Laboratory of Neurology and Oncology Drug Development, Jiangsu Simcere Pharmaceutical Co., Ltd, 699-18 Xuan Wu Avenue, Nanjing 210042, P. R. China.
PMID: 41213161 DOI: 10.1021/acs.jmedchem.5c00818
Abstract

DNA Polymerase theta (Polθ) is a key enzyme in the theta-mediated end-joining (TMEJ) and a promising target for synthetic lethality-based Cancer therapy, particularly in homologous recombination (HR)-deficient tumors. Herein, we designed and optimized a series of Polθ polymerase inhibitors, exploiting a previously unexplored binding pocket to enhance potency, cellular activity, and pharmacokinetics. Compound 33 exhibited low-nanomolar Polθ inhibition, strong antiproliferative activity in DLD1 BRCA2 KO cells, and high sensitivity to MDA-MB-436 cells. In combination with Olaparib, it significantly enhanced DNA damage accumulation, induced γH2AX levels, and achieved 85% tumor growth inhibition (TGI) in the MDA-MB-436 xenograft model. Pharmacokinetic studies confirmed a favorable dose-dependent profile, and preliminary safety evaluations indicated good tolerability. These findings establish compound 33 as a potent Polθ inhibitor with strong synthetic lethality effects, supporting its further preclinical development as a novel Polθ-targeted therapeutic agent.

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