Structure-Based identification of a potent KDM7A inhibitor exerts anticancer activity through transcriptionally reducing MKRN1 in taxol- resistant and -sensitive triple-negative breast cancer cells.

KDM7A, a histone demethylase implicated in cancer proliferation, metastasis, and drug resistance, represents a crucial therapeutic target. Utilizing "mcule.com" for virtual screening of 100,000 compounds from the ZINC database, we identified 12 compounds with high affinity for KDM7A, with compound 4 emerging as the leading candidate for effectively inhibiting KDM7A's demethylase activity. Analysis of the GTRD database, the Breast Cancer Gene Expression Miner website, and recent studies highlighted MKRN1, a gene associated with cell proliferation and drug resistance, as a key intersecting factor. Compared to 2,4-pyridine dicarboxylic acid, compound 4 significantly reduced breast cancer stem cells and induced G1 phase cell cycle arrest. Mechanistically, compound 4 inhibited KDM7A's binding to H3K27me3, decreased MKRN1 transcription, and increased the levels of cell cycle regulators p16, p21, and p27, while reducing stem cell markers ALDH1A1, CD44, and CD133. These findings suggest that compound 4 could serve as a promising lead for selective KDM7A-targeting drugs. Additionally, this study is the first to demonstrate MKRN1 as a downstream gene of KDM7A, showing significant inhibitory effects in both taxol-resistant and drug-sensitive triple-negative breast cancer (TNBC) cells. This research offers new insights into the anticancer mechanisms of KDM7A inhibitors and underscores KDM7A's potential as a therapeutic target against TNBC.