| In Vitro | In vitro activity: WM-1119 can induce cell cycle exit and cellular senescence without causing DNA damage. WM-1119 is 1,100-fold and 250-fold more active against KAT6A than against KAT5 or KAT7, respectively, and so shows greater specificity for KAT6A than does WM-8014. The testing of WM-1119 at 1 μM and 10 μM against a pharmacological panel of 159 diverse biological targets reveal no affinity. Treatment of MEFs with WM-1119 results in cell cycle arrest in G1 and a senescence phenotype similar to that seen upon treatment with WM-8014. 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. Treatment with WM-8014 or WM-1119 inhibits the proliferation of the EMRK1184 lymphoma cells in vitro, WM-1119 (IC50=0.25 μM) is ninefold more active than WM-8014 (IC50=2.3 μM), as expected on the basis of reduced protein binding.
Kinase Assay: WM-1119 is a novel, highly potent, and selective inhibitor of KAT6A/B (lysine acetyltransferase) with an IC50 value of of 0.25 μM for KAT6A, KD value of 2 nM for KAT6A, KD value of 2.2 μM for KAT5, and KD value of 0.5 μM for KAT7.
Cell Assay: Treatment of MEFs with WM-1119 resulted in cell cycle arrest in G1 and a
senescence phenotype similar to that seen upon treatment with WM-8014
(Extended Data Fig. 8). 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. |
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| In Vivo | The cohorts that are treated four times per day with WM-1119 have arrested tumour growth By day 14, with the exception of one mouse that does not respond. Spleen weights in the WM-1119-treatment group (treated four times per day) are substantially lower than spleen weights in the vehicle-treated group, and not significantly different from those of tumour-free eight-weekold mice. Treatment with WM-1119 three times per day leads to a significant reduction in tumour burden and spleen weight, but is not as effective as treatment four times per day. WM-1119 is well-tolerated; mice show no generalized ill effects and weight loss is not observed. WM-1119 treatment has no effect on haematocrit, erythrocytes or platelet numbers, but there is overall leukopenia. The proportion and overall number of tumour cells is substantially reduced by WM-1119 treatment (four times per day). |
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