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Updated: Mar 17, 2026
Direct Measurement of KDM1A Target Engagement Using Chemoprobe-based Immunoassays
Published on: June 13, 2019
Identification of potent, selective KDM5 inhibitors
Victor S Gehling1, Steven F Bellon1, Jean-Christophe Harmange1
1Constellation Pharmaceuticals, Inc., 215 First Street, Suite 200, Cambridge, MA 02142, United States.
Abstract:
This communication describes the identification and optimization of a series of pan-KDM5 inhibitors derived from compound 1, a hit initially identified against KDM4C. Compound 1 was optimized to afford compound 20, a 10nM inhibitor of KDM5A. Compound 20 is highly selective for the KDM5 enzymes versus other histone lysine demethylases and demonstrates activity in a cellular assay measuring the increase in global histone 3 lysine 4 tri-methylation (H3K4me3). In addition compound 20 has good ADME properties, excellent mouse PK, and is a suitable starting point for further optimization.
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