WM-1119

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Background

Because of the high levels of plasma-protein binding exhibited by WM-8014, WM-8014 can’t be used in vivo in mice. Development of derivatives of WM-8014 resulted in WM-1119, which has reduced plasma-protein binding. The interaction of WM-1119 with KAT6A is similar to that of WM-8014.
WM-1119 is also a highly potent, selective, reversible, and competitive inhibitor for KAT6A and KAT6B (histone lysine acetyltransferases). KD value of WM-1119 is 2 nM, compared to 5 nM for WM-8014.It is also competitive with acetyl-CoA, and driven by fast association kinetics. The structure of MYSTCryst in complex with WM-1119 was found to be almost identical to that of MYSTCryst–WM-8014.
WM-1119 induce cell cycle exit and cellular senescence without causing DNA damage. Senescence is INK4A/ARF-dependent and is accompanied by changes in gene expression that are typical of loss of KAT6A function. WM-1119, which has increased bioavailability, arrests the progression of lymphoma in mice. Notably, the activity of WM-1119 in this cell-based assay is an order of magnitude greater than WM-8014 and WM-1119 is able to induce cell cycle arrest at 1 μM. WM-1119 (IC50 0.25 μM) was ninefold more active than WM-8014 (IC50 2.3 μM), as expected on the basis of reduced protein binding.
WM-1119 is rapidly cleared after intraperitoneal injection, with the plasma concentration decreasing to below 1 μM after 4–6 h. By day 14, the cohorts that were treated four times per day with WM-1119 had arrested tumour growth. Spleen weights in the WM-1119-treatment group (treated four times per day) were substantially lower than spleen weights in the vehicle-treated group, and not significantly different from those of tumour-free eight-weekold mice.

[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.