Discovery of Novel Heterotetracyclic DNA-Dependent Protein Kinase (DNA-PK) Inhibitors with Improved Oral Bioavailability and Potent Cancer Immunotherapy-Potentiating Activity

A novel series of heterotetracyclic DNA-PK inhibitors was rationally designed, synthesized, and biologically evaluated. Most compounds showed potent DNA-PK inhibition (IC50: 10.2–88.9 nM), with lead D11 (IC50 = 10.2 nM) inducing γH2A.X upregulation and robust antiproliferative activity across six cancer cell lines. Remarkably, D11 exhibited excellent pharmacokinetics in SD rats (oral bioavailability: 42.6%; half-life: 50 h) and outperformed the clinical candidate AZD-7648 in LoVo xenografts (TGI = 72.9% vs 54.6% at 50 mg/kg, p.o.). It also synergized with anti-PD-L1 mAb to enhance CD8+ T-cell infiltration. Overall, D11 is a promising heterotetracyclic DNA-PK inhibitor with superior in vivo efficacy, favorable pharmacokinetics, and immunomodulatory potential, supporting further development.

本研究通过理性设计、合成与生物学评价，得到了一系列新型杂四环类DNA依赖蛋白激酶（DNA-PK）抑制剂。绝大多数化合物均展现出强效的DNA-PK抑制活性，半最大抑制浓度（IC50）范围为10.2~88.9 nM；其中先导化合物D11的IC50值为10.2 nM，可诱导γH2A.X表达上调，并在六种癌细胞系中表现出显著的抗增殖活性。值得注意的是，D11在SD大鼠体内展现出优异的药代动力学特性：口服生物利用度达42.6%，半衰期为50 h；在LoVo细胞异种移植瘤模型中，其疗效优于临床候选化合物AZD-7648：在50 mg/kg口服（p.o.）给药剂量下，D11的肿瘤生长抑制率（TGI）为72.9%，而AZD-7648仅为54.6%。此外，D11可与抗PD-L1单克隆抗体（anti-PD-L1 mAb）产生协同作用，增强CD8阳性T细胞的肿瘤浸润能力。综上，D11是一款极具开发前景的杂四环类DNA-PK抑制剂，其体内疗效优异、药代动力学特性良好且具备免疫调节潜力，可为其后续开发提供有力支撑。