A high-throughput screen for inhibitors of the histone acetyltransferase, KAT6A, led to identification of an aryl sulfonohydrazide derivative (CTX-0124143) that inhibited KAT6A with an IC50 of 1.0 μM. Elaboration of the structure-activity relationship and medicinal chemistry optimization led to the discovery of WM-8014 (97), a highly potent inhibitor of KAT6A (IC50 = 0.008 μM). WM-8014 competes with acetyl-CoA (Ac-CoA), and X-ray crystallographic analysis demonstrated binding to the Ac-CoA binding site. Through inhibition of KAT6A activity, WM-8014 induces cellular senescence and represents a unique pharmacological tool.
Bibliographical noteFunding Information:
The National Health and Medical Research Council of Australia (NHMRC) is thanked for Research Support (#1030704, 1080146) and Fellowship support for J.B. (2012–2016 Senior Research Fellowship #1020411, 2017—Principal Research Fellowship #1117602). Acknowledged is Australian Federal Government Education Investment Fund Super Science Initiative and the Victorian State Government, Victoria Science Agenda Investment Fund for infrastructure support and the facilities and the scientific and technical assistance of the Australian Translational Medicinal Chemistry Facility (ATMCF), Monash Institute of Pharmaceutical Sciences (MIPS). ATMCF is supported by Therapeutic Innovation Australia (TIA). TIA is supported by the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program. We thank Dr Matthew Chung for his efforts in discovering the first crystals of MOZ mutants. This research was partly undertaken on the MX2 beamline at the Australian Synchrotron, Victoria, Australia. We thank the beamline staff for their assistance. Funding from the Victorian Government Operational Infrastructure Support Scheme to St Vincent’s Institute is gratefully acknowledged. M.W.P. is a National Health and Medical Research Council of Australia Research Fellow.