Research Publications


Discovery of Benzoylsulfonohydrazides as potent inhibitors of the histone acetyltransferase KAT6A

Leaver, DJ; Cleary, B; Nguyen, N; Priebbenow, DL; Lagiakos, HR; Sanchez, J; Xue, L; Huang, F; Sun, Y; Mujumdar, P; Mudududdla, R; Varghese, S; Teguh, S; Charman, SA; White, KL; Katneni, K; Cuellar, M; Strasser, JM; Dahlin, JL; Walters, MA; Street, IP; Monahan, BJ; Jarman, KE; Sabroux, HJ; Falk, H; Chung, MC; Hermans, SJ; Parker, MW; Thomas, T; Baell, JB
Journal of Medicinal Chemistry
Journal Article
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 muM. 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 muM). 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.
Personalised Oncology; Advanced Technology and Biology; Epigenetics and Development
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Creation Date 2019-09-20 10:16:33 Last Modified 2019-09-24 03:49:16