PDF(Pubmed)
Abstract：
The dominant role of non-homologous end-joining in the repair of radiation-induced double-strand breaks identifies DNA-dependent protein kinase (DNA-PK) as an excellent target for the development of radiosensitizers. We report the discovery of a new class of imidazo[4,5-c]pyridine-2-one DNA-PK inhibitors. Structure-activity studies culminated in the identification of 78 as a nM DNA-PK inhibitor with excellent selectivity for DNA-PK compared to related phosphoinositide 3-kinase (PI3K) and PI3K-like kinase (PIKK) families and the broader kinome, and displayed DNA-PK-dependent radiosensitization of HAP1 cells. Compound 78 demonstrated robust radiosensitization of a broad range of cancer cells in vitro, displayed high oral bioavailability, and sensitized colorectal carcinoma (HCT116/54C) and head and neck squamous cell carcinoma (UT-SCC-74B) tumor xenografts to radiation. Compound 78 also provided substantial tumor growth inhibition of HCT116/54C tumor xenografts in combination with radiation. Compound 78 represents a new, potent, and selective class of DNA-PK inhibitors with significant potential as radiosensitizers for cancer treatment.
摘要：
非同源末端连接在修复辐射诱导的双链断裂中的主导作用将DNA依赖性蛋白激酶（DNA-PK）确定为开发放射增敏剂的出色靶标。我们报道了一类新的咪唑并[4,5-c]吡啶-2-酮DNA-PK抑制剂的发现。与相关的磷酸肌醇3激酶（PI3K）和PI3K样激酶（PIKK）家族和更广泛的激酶相比，结构活性研究最终确定了78作为nMDNA-PK抑制剂，对DNA-PK具有优异的选择性。并显示HAP1细胞的DNA-PK依赖性放射增敏作用。化合物78在体外证明了对多种癌细胞的强大放射增敏作用。显示出高口服生物利用度，和致敏的结直肠癌(HCT116/54C)和头颈部鳞状细胞癌(UT-SCC-74B)肿瘤异种移植物对放射。化合物78还与放射组合提供了对HCT116/54C肿瘤异种移植物的显著肿瘤生长抑制。化合物78代表一种新的，强力，和选择性的DNA-PK抑制剂类，具有作为癌症治疗的放射增敏剂的巨大潜力。
