2. Academic Validation
  3. 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

  • Eur J Med Chem. 2023 Nov 15;260:115770. doi: 10.1016/j.ejmech.2023.115770.
Yongtao Duan 1,  Yabiao Zhao 2,  Zhenzhen Li 3,  Zhenling Liu 1,  Mingzhu Wang 1,  Xuan Wang 3,  Moran Sun 4,  Chuanjun Song 5,  Yongfang Yao 6
Affiliations

Affiliations

  • 1 Henan Provincial Key Laboratory of Pediatric Hematology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou, 450018, China.
  • 2 College of Chemistry, and Green Catalysis Center, Zhengzhou University, Zhengzhou, 450001, China.
  • 3 School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, China.
  • 4 School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, China. Electronic address: sunmr@zzu.edu.cn.
  • 5 College of Chemistry, and Green Catalysis Center, Zhengzhou University, Zhengzhou, 450001, China. Electronic address: chjsong@zzu.edu.cn.
  • 6 Henan Provincial Key Laboratory of Pediatric Hematology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou University, Zhengzhou, 450018, China; School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, Henan, 450001, China. Electronic address: yongfangyao@zzu.edu.cn.
PMID: 37651878 DOI: 10.1016/j.ejmech.2023.115770
Abstract

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.

Keywords

Isosteres; KAT6A; Leukemia; SAR.

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