Identification of 6-Anilino Imidazo[4,5-c]pyridin-2-ones as Selective DNA-Dependent Protein Kinase Inhibitors and Their Application as Radiosensitizers,Journal of Medicinal Chemistry

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Identification of 6-Anilino Imidazo[4,5-c]pyridin-2-ones as Selective DNA-Dependent Protein Kinase Inhibitors and Their Application as Radiosensitizers
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-07-15 , DOI: 10.1021/acs.jmedchem.4c01120
Cho R Hong ₁ , Lydia P Liew ₁ , Way W Wong ₁ , Benjamin D Dickson ₂ , Gary Cheng ₁ , Avik Shome ₁ , Rebecca Airey ₁ , Jagdish Jaiswal ₁ , Barbara Lipert ₁ , Stephen M F Jamieson ₁ , William R Wilson ₁ , Michael P Hay ₁

Affiliation

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.

中文翻译：

6-苯胺基咪唑并[4,5-c]吡啶-2-酮作为选择性 DNA 依赖性蛋白激酶抑制剂的鉴定及其作为放射增敏剂的应用

非同源末端连接在修复辐射引起的双链断裂中的主导作用使 DNA 依赖性蛋白激酶 (DNA-PK) 成为开发放射增敏剂的绝佳靶点。我们报告发现了一类新的咪唑并[4,5- c ]吡啶-2-酮 DNA-PK 抑制剂。结构-活性研究最终鉴定出78 种nM DNA-PK 抑制剂，与相关的磷酸肌醇 3-激酶 (PI3K) 和 PI3K 样激酶 (PIKK) 家族以及更广泛的激酶组相比，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。化合物78在体外对多种癌细胞表现出强大的放射增敏作用，表现出高口服生物利用度，并使结直肠癌 (HCT116/54C) 和头颈鳞状细胞癌 (UT-SCC-74B) 肿瘤异种移植物对放射敏感。化合物78与放射组合还对HCT116/54C肿瘤异种移植物提供显着的肿瘤生长抑制。化合物78代表了一类新型、有效、选择性的 DNA-PK 抑制剂，具有作为癌症治疗放射增敏剂的巨大潜力。

更新日期：2024-07-15

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