Discovery of benzoylsulfonohydrazides as potent inhibitors of the histone acetyltransferase KAT6A

David J. Leaver, Benjamin Cleary, Nghi Nguyen, Daniel 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 Cuellar, Jessica M. Strasser, Jayme L. Dahlin, Michael A. WaltersIan P. Street, Brendon J. Monahan, Kate E. Jarman, Helene Jousset Sabroux, Hendrik Falk, Matthew C. Chung, Stefan J. Hermans, Michael W. Parker, Tim Thomas, Jonathan B. Baell

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5 Citations (Scopus)

Abstract

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 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 (IC50 = 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.

Original languageEnglish
Pages (from-to)7146-7159
Number of pages14
JournalJournal of Medicinal Chemistry
Volume62
Issue number15
DOIs
Publication statusPublished - 8 Aug 2019

Cite this

Leaver, D. J., Cleary, B., Nguyen, N., Priebbenow, D., Lagiakos, H. R., Sanchez, J., Xue, L., Huang, F., Sun, Y., Mujumdar, P., Mudududdla, R., Varghese, S., Teguh, S., Charman, S. A., White, K. L., Katneni, K., Cuellar, M., Strasser, J. M., Dahlin, J. L., ... Baell, J. B. (2019). Discovery of benzoylsulfonohydrazides as potent inhibitors of the histone acetyltransferase KAT6A. Journal of Medicinal Chemistry, 62(15), 7146-7159. https://doi.org/10.1021/acs.jmedchem.9b00665