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.

针对组蛋白乙酰转移酶KAT6A（histone acetyltransferase KAT6A）的高通量筛选，成功获得一种芳基磺酰肼衍生物CTX-0124143，其对KAT6A的半抑制浓度（IC50）为1.0 μM。通过构效关系研究与药物化学优化，最终得到高活性KAT6A抑制剂WM-8014（编号97），其对KAT6A的IC50值低至0.008 μM。WM-8014可与乙酰辅酶A（acetyl-CoA，Ac-CoA）竞争结合位点，X射线晶体学分析证实其结合于乙酰辅酶A结合区域。通过抑制KAT6A的酶活性，WM-8014可诱导细胞衰老，是一种独特的药理学研究工具。