Screening for small molecule degraders of KDM5A & B

National Center For Advancing Translational Sciences

Investigators

Abstract

The goal of this project is to identify specific degraders of the histone demethylases, KDM5A & B, which catalyze the demethylation of lysine 4 on histone H3 (H3K4me3/2) and thereby regulate numerous genes involved in cell differentiation and development. Both KDM5A and KDM5B are overexpressed in a variety of cancers and are implicated in cancer cell growth, metastasis, drug resistance, and in vivo tumor growth. Previous efforts to develop small molecule inhibitors of KDM5A & B enzymatic activity have failed due to lack of specificity. Using a different approach, this project will employ cell-based assays to monitor KDM5A/B protein steady state levels in living cells and screen for compounds that reduce protein levels through selective degradation of the target protein. To date, we have screened our drug repurposing libraries and identified several hits that have been validated by western blotting to reduce KDM5A & B protein levels in a breast cancer cell line. The project team has since expanded our screening and identified several novel chemotypes demonstrating potent, selective modulation of KDM5A & B.Current efforts include hit analog testing and profiling.