WM-8014

WM-8014 (WM8014) is a highly potent, selective inhibitor of lysine acetyltransferase KAT6A with Kd of 5 nM and IC50 of 8 nM; WM-8014 is reversible competitor of acetyl coenzyme A and inhibits MYST-catalysed histone acetylation, also inhibits closely related KAT6B (IC50=28 nM), displays >10-fold selectivity over KAT7 and KAT5 (IC50=342 nM and 224 nM), shows no inhibition against KAT8, KAT2A, KAT2B, KAT3A and KAT3B; induces cell cycle exit and cellular senescence without causing DNA damage, reduces acetylation of specific histone lysine residues and changes in gene expression that resemble the genetic loss of KAT6A; selectively reduces liver volume in a zebrafish model of KRASG12V-driven hepatocellular overproliferation, robustly upregulate the cell cycle regulators Cdkn2a and Cdkn1a in hepatocytes. (In Vitro) :WM-8014 (Compound 36) is an inhibitor of MOZ, with an IC50 of 55 nM. WM-8014 causes cell senescence and suppresses the proliferation with IC50s of 1.6 μM and 551 nM, respectively. WM-8014 also reduces mRNA coding for the MOZ gene Cdc6 by 65.1%.