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

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

Journal of medicinal chemistry (2020-03-03)

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

PMID32118427

摘要

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.