Research Publications


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

Priebbenow, DL; Leaver, DJ; Nguyen, N; Cleary, B; Lagiakos, HR; Sanchez, J; Xue, L; Huang, F; Sun, Y; Mujumdar, P; Mudududdla, R; Varghese, S; Teguh, S; Charman, SA; White, KL; Shackleford, DM; Katneni, K; Cuellar, M; Strasser, JM; Dahlin, JL; Walters, MA; Street, IP; Monahan, BJ; Jarman, KE; Jousset Sabroux, H; Falk, H; Chung, MC; Hermans, SJ; Downer, NL; Parker, MW; Voss, AK; Thomas, T; Baell, JB
Journal of Medicinal Chemistry
Journal Article
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 muM. 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 muM), competes with Ac-CoA by binding to the Ac-CoA binding site, and has an oral bioavailability of 56% in rats.
Personalised Oncology; Advanced Technology and Biology
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Creation Date 2020-05-04 11:46:53 Last Modified 2020-05-04 02:11:08