Discovery of Benzoylsulfonohydrazides as Potent Inhibitors of the Histone Acetyltransferase KAT6A.
David J LeaverBenjamin ClearyNghi NguyenDaniel L PriebbenowH Rachel LagiakosJulie SanchezLian XueFei HuangYuxin SunPrashant MujumdarRamesh MudududdlaSwapna VargheseSilvia TeguhSusan A CharmanKaren L WhiteKasiram KatneniMatthew CuellarJessica M StrasserJayme L DahlinMichael A WaltersIan P StreetBrendon J MonahanKate E JarmanHelene Jousset SabrouxHendrik FalkMatthew C ChungStefan J HermansMichael W ParkerTim ThomasJonathan B BaellPublished in: Journal of medicinal chemistry (2019)
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.