Discovery of Benzoylsulfonohydrazides as Potent Inhibitors of the Histone Acetyltransferase KAT6A

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.