Targeting ATP catalytic activity of chromodomain helicase CHD1L for the anticancer inhibitor discovery

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.