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 Compound 6j. Compared to CTX-0124143, 6j showed a 16-fold stronger inhibition of KAT6A (0.49 μM vs. 0.03 μM) with high selectivity. In addition, 6j exhibited strong antitumor activity on four leukemia cell lines. Moreover, 6j showed significant improvement in metabolic stability and pharmacokinetics in vivo and in vitro. In conclusion, 6j shows excellent potential as a promising anti-leukemia drug candidate.

KAT6A已被确定为白血病治疗的新靶点。KAT6A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至关重要，突变或易位被认为是白血病发生的主要原因之一。在之前的研究中，CTX-0124143已被证明是一类具有磺酰肼骨架的KAT6A抑制剂。但活性弱、选择性差以及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NC键取代，并且两侧的芳香环被取代。最终，我们得到了化合物6j。与 CTX-0124143 相比，6j对 KAT6A 的抑制作用强 16 倍（0.49 μM vs. 0.03 μM），且具有高选择性。此外，6j对四种白血病细胞系表现出很强的抗肿瘤活性。此外，6j在体内和体外的代谢稳定性和药代动力学方面均表现出显着改善。总之，6j显示出作为有前途的抗白血病候选药物的巨大潜力。