Identification of Novel Small-Molecule Inhibitors Targeting KDM5B and Evaluation of Their Antitumour Effects

KDM5B, a member of the KDM5 family of histone demethylases, plays a critical role in transcriptional repression by demethylating H3K4me2/3. It regulates key biological processes such as development, stem cell maintenance, and oncogenesis, and its aberrant expression is implicated in various cancers. Accordingly, KDM5B is considered a promising therapeutic target in cancer drug discovery. In this study, we performed a screening to identify novel inhibitors of KDM5B. Through this screening, we identified a common core scaffold associated with KDM5B inhibitory activity, and subsequent optimization of the side-chain structures led to the identification of a series of compounds with IC₅₀ values ranging from several nanomolar to several micromolar. Evaluation of growth inhibitory activity using the JFCR39 human cancer cell line panel revealed that the final lead compounds, JB-157 and JB-161, exhibited GI₅₀ values in the low micromolar range. In a xenograft model, where the human colorectal cancer cell line HT-29 was implanted into NOD/SCID mice, administration of these compounds resulted in antitumour effects, with JB-161 showing particularly pronounced tumor suppression in a subset of treated animals. Furthermore, combination treatment with in vivo CAR-T cell therapy and JB-161 in C57BL/6J mice was associated with alterations in chromatin accessibility in tumor and immune cell populations. Taken together, these results suggest that JB-161 is a candidate KDM5B inhibitor associated with chromatin accessibility changes and antitumour activity.