Design， Synthesis， and Biological Evaluation of Lysine Demethylase 5 C Degraders

摘要

Lysine demethylase 5 C(KDM5C)controls epigenetic gene expression and is attracting great interest in the field of chemical epigenetics.KDM5C has emerged as a therapeutic target for anti-prostate cancer agents， and recently we identified triazole 1 as an inhibitor of KDM5C.Compound 1 exhibited highly potent KDM5C-inhibitory activity in in vitro enzyme assays， but did not show strong anticancer effects.Therefore， a different approach is needed for the development of anticancer agents targeting KDM5C.Here， we attempted to identify KDM5C degraders by focusing on a protein-knockdown strategy.Compound 3b， which was designed based on compound 1， degraded KDM5C and inhibited the growth of prostate cancer PC-3 cells more strongly than compound 1.These findings suggest that KDM5C degraders are more effective as anticancer agents than compounds that only inhibit the catalytic activity of KDM5C.