Discovery of N-(2-oxoethyl) sulfanilamide-derived inhibitors of KAT6A (MOZ) against leukemia by an isostere strategy.

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.