WM-1119 is a highly potent, selective KAT6A/B inhibitor

KAT6A:0.25 μM, KAT6A:2 nM(KD), KAT5:2.2 μM(KD), KAT7:0.5 μM(KD)

WM-1119可诱导细胞周期退出和细胞衰老，而不会造成DNA损伤。与KAT5或KAT7相比，WM-1119对KAT6A的活性分别高出1,100倍和250倍，因此显示出较WM-8014更高的KAT6A专一性。在对159种不同生物靶标的药理学面板进行测试时，WM-1119在1 μM和10 μM浓度下均未显示亲和力。WM-1119处理MEFs可导致G1期的细胞周期阻滞和衰老表型，类似于WM-8014处理时所见。值得注意的是，WM-1119在这个基于细胞的检测中的活性比WM-8014高一个数量级，且WM-1119能在1 μM浓度下诱导细胞周期阻滞。WM-8014或WM-1119的处理抑制了体外EMRK1184淋巴瘤细胞的增殖，WM-1119（IC50=0.25 μM）的活性是WM-8014（IC50=2.3 μM）的九倍，这与其降低的蛋白质结合能力一致。

雄性C57BL/6-白化(B6(Cg)-Tyrc-2J/J)小鼠通过静脉注射100,000个转染有荧光素酶表达构建的EMRK1184细胞，以监测淋巴瘤的生长。淋巴瘤细胞移植后三天，所有小鼠显示荧光素酶活性，这表明淋巴瘤细胞的扩增。随后，小鼠被随机分为不同浓度（1, 2.5, 5, 10 μM）的WM-1119治疗组和对照组。由于WM-1119在腹腔注射后迅速被清除，血浆浓度在4-6小时后降至1 μM以下，故小鼠每8小时（每天三次，每个治疗组两个队列，每队列三只小鼠）或每6小时（每天四次，两个队列，每队列分别三只和六只小鼠）注射。到第14天，每天四次接受WM-1119治疗的队列成功抑制了肿瘤生长，但有一只小鼠未响应。每天四次接受WM-1119治疗的小鼠脾脏重量显著低于对照组，并与无肿瘤的八周龄小鼠无显著差异。每天三次治疗虽然明显减轻了肿瘤负担和脾脏重量，但效果不如每天四次治疗。WM-1119具有良好的耐受性；小鼠未显示出一般性不适，无体重损失。WM-1119治疗对红细胞比容、红细胞或血小板数量无影响，但总体上出现白细胞减少。通过每天四次WM-1119治疗，肿瘤细胞的比例和总数显著减少。

Male C57BL/6-albino (B6(Cg)-Tyrc-2J/J) mice are injected intravenously with 100,000 EMRK1184 cells transfected with a luciferase-expression construct. Lymphoma growth is monitored. Three days after the lymphomacell transplant, all mice show luciferase activity, which indicate the expansion of lymphoma cells. Mice are then divided randomly into WM-1119-treatment with different conentrations (1, 2.5, 5, 10 μM) and vehicle-control groups. Because WM-1119 is rapidly cleared after intraperitoneal injection, with the plasma concentration decreasing to below 1 μM after 4-6 h cohorts of mice are injected every 8 h (three times per day, two cohorts of three mice per treatment group) or every 6 h (four times per day, two cohorts of three and six mice per treatment group).By day 14, the cohorts that are treated four times per day with WM-1119 have arrested tumour growth, 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).