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

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.

DNA聚合酶θ（Polθ）是介导微同源末端连接（MMEJ）的关键酶，在多种人类癌症中过表达，是极具潜力的治疗靶点，尤其适用于同源重组（HR）缺陷型肿瘤。本文报道了一类以芳基炔为骨架的新型Polθ聚合酶（Polθ-pol）抑制剂的发现与优化过程，该骨架可延伸至聚合酶结构域内的外周通道，以增强靶点结合能力。在所合成的化合物中，化合物20对Polθ-pol展现出纳摩尔级的强效抑制活性（半数抑制浓度IC50 = 1.3 nM），同时对MDA-MB-436、Capan-1及DLD-1（BRCA2–/–）等同源重组缺陷型癌细胞系具有抗增殖活性。此外，化合物20表现出良好的药代动力学特性：小鼠体内口服生物利用度为103.36%，大鼠体内为63.71%。在MDA-MB-436异种移植模型中，化合物20可显著抑制肿瘤生长且未观察到明显毒性。上述研究结果表明，芳基炔骨架是开发口服活性Polθ靶向治疗药物的极具前景的策略。