Discovery of Novel Orally Bioavailable Polθ Inhibitors with Arylalkyne Scaffolds for Targeting HR-Deficient Cancers

  • J Med Chem. 2026 Feb 12;69(3):2215-2237. doi: 10.1021/acs.jmedchem.5c01977.
Jinyang Zhang  1  2 ,  Xiaomeng Sun  1  2 ,  Qichen Zhou  1  2 ,  Yingying Wei  1  2 ,  Biao Chen  1  3 ,  Junhui Jiao  1  2 ,  Yu Du  1  2 ,  Shepherd Wufoyrwoth  2 ,  Haoze Chi  1  2 ,  Yi Yang  1  2 ,  Ping Wei  4 ,  Yungen Xu  1  2  3 ,  Yi Zou  1  2  3 ,  Qihua Zhu  1  2
Affiliations
  • 1. State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China.
  • 2. Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
  • 3. Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 211198, China.
  • 4. Hefei Institute of Pharmaceutical Industry Co., Ltd., Hefei 230601, China.
PMID: 41611653 DOI: 10.1021/acs.jmedchem.5c01977
Abstract

Polθ, a key enzyme mediating microhomology-mediated end joining (MMEJ), is overexpressed in multiple human cancers and represents a promising therapeutic target, particularly in tumors with homologous recombination (HR) deficiency. Herein, we report the discovery and optimization of a novel series of Polθ polymerase (Polθ-pol) inhibitors featuring an arylalkyne scaffold, which extends into a peripheral channel within the polymerase domain to enhance target engagement. Among the synthesized compounds, compound 20 exhibited potent inhibitory activity against Polθ-pol at a nanomolar level (IC50 = 1.3 nM), along with antiproliferative activity against the HR-deficient Cancer cell lines, such as MDA-MB-436, Capan-1, and DLD-1 (BRCA2-/-). Moreover, compound 20 demonstrated favorable pharmacokinetic properties, with oral bioavailability values of 103.36% in mice and 63.71% in rats, respectively. In an MDA-MB-436 xenograft model, compound 20 significantly suppressed tumor growth without evident toxicity. These findings underscore the arylalkyne scaffold as a highly promising strategy for the development of orally active Polθ-targeted therapeutics.

Products