2. Academic Validation
  3. Discovery of Novel Orally Bioavailable Polθ Inhibitors with Arylalkyne Scaffolds for Targeting HR-Deficient Cancers

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

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.

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