CHD1L 充当 ATP 依赖性染色质重塑酶，具有由双链 DNA 激活的 ATP 酶催化结构域。它参与癌症进展的关键方面，例如耐药性和上皮间质转化，强调了其作为癌症治疗有前景的治疗靶点的潜力。在这项研究中，我们开创了一种创新方法，将多种深度学习方法与生化和细胞实验相结合，以确定有前途的 CHD1L 抑制剂。通过虚拟筛选超过 150 万种小分子化合物，我们精心挑选了 36 种候选化合物，并对前 13 种候选化合物进行了严格评估。我们的研究结果表明，先导化合物 C071-0684 是一种具有新型分子骨架的有效抗癌药物，对靶向 CHD1L 的结直肠癌细胞和乳腺癌细胞表现出显着功效。该化合物对 ATP 酶活性和与 CHD1Li 6.11 的结合亲和力具有相当的影响，凸显了其卓越的药理学潜力。这些结果提供了宝贵的见解，为 CHD1L 靶向疗法的发现和开发铺平了道路，为癌症患者带来了巨大的希望。版权所有 © 2024。由 Elsevier B.V. 出版。

CHD1L functions as an ATP-dependent chromatin remodeling enzyme, featuring an ATPase catalytic domain activated by double-stranded DNA. Its involvement in critical aspects of cancer progression, such as drug resistance and epithelial-mesenchymal transition, underscores its potential as a promising therapeutic target for cancer treatment. In this study, we have pioneered an innovative approach that integrates multiple deep learning methodologies alongside biochemical and cellular experiments to identify promising inhibitors of CHD1L. Through virtual screening of over 1.5 million small molecule compounds, we carefully curated a set of 36 candidate compounds and rigorously evaluated the top 13 candidates. Our findings establish the lead compound C071-0684 as a potent anticancer agent with a novel molecular backbone, demonstrating remarkable efficacy against colorectal and breast cancer cells targeting CHD1L. This compound exhibited a comparable effect on ATPase activity and binding affinity with CHD1Li 6.11, highlighting its superior pharmacological potential. These results provide valuable insights and pave the way for the discovery and development of CHD1L-targeted therapeutics, holding great promise for cancer patients.Copyright © 2024. Published by Elsevier B.V.