WM-8014

WM-8014 is a highly potent, selective, reversible, and competitive inhibitor for KAT6A and KAT6B (histone lysine acetyltransferases). WM-8014 selectively inhibits KAT6A, KAT6B, KAT5 and KAT7 with the IC₅₀ of 8 nM, 28 nM, 224 nM and 342 nM, respectively. WM-8014 could soluble in water up to about 8–16 μM.

WM-8014 competes directly with acetyl-CoA in the substrate-binding domain. The WM-8014 molecule occupies the acetyl-CoA-binding site on MYST^Cryst. The core acyl sulfonyl hydrazide moiety of WM-8014 makes similar hydrogen bonds to MYST^Cryst as the diphosphate group of acetyl-CoA does.

WM-8014 could induce cell cycle arrest in embryonic day (E)14.5 mouse embryonic fibroblasts (MEFs). RNA sequencing (RNA-seq) of MEFs treated with WM-8014 revealed a signature of cellular senescence, including upregulated expression of Cdkn2a mRNA and decreased expression of Cdc6, which is a KAT6A target gene and a regulator of DNA replication. WM-8014 acts through the p16^INK4A–p19^ARF pathway, causing irreversible cell cycle exit leading to senescence, and doesn’t have a general cytotoxic effect.

In a zebrafish model of KRAS^G12V-driven hepatocellular overproliferation, researchers observed a significant, concentration-dependent reduction in liver volume in response to treatment with WM-8014, and a substantial reduction in hepatocytes in S phase. Notably, WM-8014 did not impair the growth of the normal liver. Therefore, WM-8014 potentiates oncogene-induced senescence, but it does not affect normal hepatocyte growth.

However, the high levels of plasma-protein binding exhibited by WM-8014 precluded in vivo studies in mice. If you want to analysis the effect of WM-8014 in vivo, please turn to its derivative WM-1119.

References:

[1]. Baell JB1,2, Leaver DJ3，et, al, Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth. Nature. 2018 Aug;560(7717):253-257. doi: 10.1038/s41586-018-0387-5. Epub 2018 Aug 1.

[2]. Falk H1, Connor T, et, al, An efficient high-throughput screening method for MYST family acetyltransferases, a new class of epigenetic drug targets. J Biomol Screen. 2011 Dec;16(10):1196-205. doi: 10.1177/1087057111421631. Epub 2011 Nov 14.