Journal of Medicinal Chemistry p. 7146 - 7159 (2019)
Update date:2022-08-15
Topics:
Leaver, David J.
Cleary, Benjamin
Nguyen, Nghi
Priebbenow, Daniel L.
Lagiakos, H. Rachel
Sanchez, Julie
Xue, Lian
Huang, Fei
Sun, Yuxin
Mujumdar, Prashant
Mudududdla, Ramesh
Varghese, Swapna
Teguh, Silvia
Charman, Susan A.
White, Karen L.
Katneni, Kasiram
Cuellar, Matthew
Strasser, Jessica M.
Dahlin, Jayme L.
Walters, Michael A.
Street, Ian P.
Monahan, Brendon J.
Jarman, Kate E.
Sabroux, Helene Jousset
Falk, Hendrik
Chung, Matthew C.
Hermans, Stefan J.
Parker, Michael W.
Thomas, Tim
Baell, Jonathan B.
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.
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