Discovery of Benzoylsulfonohydrazides as Potent Inhibitors of the Histone Acetyltransferase KAT6A

作者：David J. Leaver, Benjamin Cleary, Nghi Nguyen, Daniel L. Priebbenow, H. Rachel Lagiakos, Julie Sanchez, Lian Xue, Fei Huang, Yuxin Sun, Prashant Mujumdar, Ramesh Mudududdla, Swapna Varghese, Silvia Teguh, Susan A. Charman, Karen L. White, Kasiram Katneni, Matthew E. Cuellar, Jessica M. Strasser, Jayme L. Dahlin, Michael A. Walters, Ian P. Street, Brendon J. Monahan, Kate E. Jarman, Hélène Jousset Sabroux, Hendrik Falk, Matthew Chung, S.J. Hermans, Michael W. Parker, Tim Thomas, Jonathan B. Baell · 发表于：Journal of Medicinal Chemistry · 年份：2019 · DOI：10.1021/acs.jmedchem.9b00665 · 被引用次数：40 · 研究领域：Histone Deacetylase Inhibitors Research、Genomics and Chromatin Dynamics、Protein Degradation and Inhibitors

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 IC 50 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 (IC 50 = 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.