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鉴定 6-苯胺咪唑并[4,5-]吡啶-2-酮类化合物作为选择性的 DNA 依赖性蛋白激酶抑制剂及其作为放射增敏剂的应用。

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

机构信息

Auckland Cancer Society Research Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.

Chemistry and Applied Physics, School of Science, University of Waikato, Private Bag 3105, Hamilton 3240, New Zealand.

出版信息

J Med Chem. 2024 Jul 25;67(14):12366-12385. doi: 10.1021/acs.jmedchem.4c01120. Epub 2024 Jul 15.

DOI:10.1021/acs.jmedchem.4c01120
PMID:39007759
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11284801/
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-]pyridine-2-one DNA-PK inhibitors. Structure-activity studies culminated in the identification of 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 demonstrated robust radiosensitization of a broad range of cancer cells , 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 also provided substantial tumor growth inhibition of HCT116/54C tumor xenografts in combination with radiation. Compound 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起主导作用，这表明 DNA 依赖性蛋白激酶（DNA-PK）是开发放射增敏剂的优秀靶点。我们报告了一类新型咪唑并[4,5-]吡啶-2-酮 DNA-PK 抑制剂的发现。构效关系研究的最终结果是确定 为一种具有纳摩尔效力的 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，并且表现出对 HAP1 细胞的 DNA-PK 依赖性放射增敏作用。化合物 对广泛的癌细胞表现出强大的放射增敏作用 ，具有高口服生物利用度，并使结直肠癌（HCT116/54C）和头颈部鳞状细胞癌（UT-SCC-74B）肿瘤异种移植物对辐射敏感。化合物 还与辐射联合对 HCT116/54C 肿瘤异种移植物的肿瘤生长有显著抑制作用。化合物 代表了一类新型、有效且选择性的 DNA-PK 抑制剂，具有作为癌症治疗放射增敏剂的巨大潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0057/11284801/cdda29b352de/jm4c01120_0014.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0057/11284801/cdda29b352de/jm4c01120_0014.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0057/11284801/c0e9057b6303/jm4c01120_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0057/11284801/b30bbfce6927/jm4c01120_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0057/11284801/964d8e9c9bcd/jm4c01120_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0057/11284801/0a7d54ee378e/jm4c01120_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0057/11284801/8034d258cdc4/jm4c01120_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0057/11284801/f45a2d5018f2/jm4c01120_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0057/11284801/fd95ce609006/jm4c01120_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0057/11284801/52871f358338/jm4c01120_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0057/11284801/c8a4cb1528c7/jm4c01120_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0057/11284801/b5055e06fd3f/jm4c01120_0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0057/11284801/dfaaa5c6ca97/jm4c01120_0011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0057/11284801/9ed545aca1df/jm4c01120_0012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0057/11284801/24ead80fdddb/jm4c01120_0013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0057/11284801/cdda29b352de/jm4c01120_0014.jpg

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