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Discovery of Acylsulfonohydrazide-Derived Inhibitors of the Lysine Acetyltransferase, KAT6A, as Potent Senescence-Inducing Anti-Cancer Agents

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posted on 19.03.2020 by Daniel L. Priebbenow, David J. Leaver, Nghi Nguyen, Benjamin Cleary, 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, David M. Shackleford, Kasiram Katneni, Matthew Cuellar, Jessica M. Strasser, Jayme L. Dahlin, Michael A. Walters, Ian P. Street, Brendon J. Monahan, Kate E. Jarman, Helene Jousset Sabroux, Hendrik Falk, Matthew C. Chung, Stefan J. Hermans, Natalie L. Downer, Michael W. Parker, Anne K. Voss, Tim Thomas, Jonathan B. Baell
A high-throughput screen designed to discover new inhibitors of histone acetyltransferase KAT6A uncovered CTX-0124143 (1), a unique aryl acylsulfonohydrazide with an IC50 of 1.0 μM. Using this acylsulfonohydrazide as a template, we herein disclose the results of our extensive structure–activity relationship investigations, which resulted in the discovery of advanced compounds such as 55 and 80. These two compounds represent significant improvements on our recently reported prototypical lead WM-8014 (3) as they are not only equivalently potent as inhibitors of KAT6A but are less lipophilic and significantly more stable to microsomal degradation. Furthermore, during this process, we discovered a distinct structural subclass that contains key 2-fluorobenzenesulfonyl and phenylpyridine motifs, culminating in the discovery of WM-1119 (4). This compound is a highly potent KAT6A inhibitor (IC50 = 6.3 nM; KD = 0.002 μM), competes with Ac-CoA by binding to the Ac-CoA binding site, and has an oral bioavailability of 56% in rats.