Discovery of N-(2-oxoethyl) sulfanilamide-derived inhibitors of KAT6A (MOZ) against leukemia by an isostere strategy.
Discovery of N-(2-oxoethyl) sulfanilamide-derived inhibitors of KAT6A (MOZ) against leukemia by an isostere strategy.
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DOI：
10.1016/j.ejmech.2023.115770
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发表时间：
2023-08
影响因子：
6.7
通讯作者：
Y. Duan;Yabiao Zhao;Zhenzhen Li;Zhenling Liu;Mingzhu Wang;Xuan Wang;Moran Sun;Chuanjun Song;Yongfang Yao
中科院分区：
文献类型：
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作者：
Y. Duan;Yabiao Zhao;Zhenzhen Li;Zhenling Liu;Mingzhu Wang;Xuan Wang;Moran Sun;Chuanjun Song;Yongfang Yao
KAT 6A已被确定为白血病治疗的新靶点。KAT 6A的组蛋白乙酰转移酶活性对于正常造血干细胞的自我更新是必不可少的，并且突变或易位被认为是白血病发展的主要原因之一。在先前的研究中，CTX-0124143已被证明是一类具有磺酰肼骨架的KAT 6A抑制剂。但活性弱、选择性差和药代动力学问题阻碍了其临床应用。在这项工作中，化合物CTX-0124143中的N-N键被N-C键取代，两侧的芳环被取代。最后，我们得到化合物6 j。与CTX-0124143相比，6 j显示出对KAT 6A的16倍强抑制（0.49 μM vs. 0.03 μM），具有高选择性。此外，6 j对4种白血病细胞株均表现出较强的抗肿瘤活性。此外，6 j在体内和体外的代谢稳定性和药代动力学方面显示出显著改善。总之，6 j显示出作为一种有希望的抗白血病候选药物的优异潜力。
KAT6A has been identified as a new target for leukemia treatment. The histone acetyltransferase activity of KAT6A is essential for normal hematopoietic stem cell self-renewal, and mutations or translocations are regarded as one of the major causes of leukemia development. In previous studies, CTX-0124143 has been shown to be a class of KAT6A inhibitors with a sulfonyl hydrazide backbone. However, weak activity, poor selectivity and pharmacokinetic problems have hindered its clinical application. In this work, the N‒N bond in compound CTX-0124143 was replaced by an N-C bond, and the aromatic rings were replaced on both sides. Finally, we obtained Compound6j. Compared to CTX-0124143,6jshowed a 16-fold stronger inhibition of KAT6A (0.49 μM vs. 0.03 μM) with high selectivity. In addition,6jexhibited strong antitumor activity on four leukemia cell lines. Moreover,6jshowed significant improvement in metabolic stability and pharmacokinetics in vivo and in vitro. In conclusion,6jshows excellent potential as a promising anti-leukemia drug candidate.