Discovery of Pyrazolo[1,5- a]pyrimidine Derivative as a Novel and Selective ALKBH5 Inhibitor for the Treatment of AML

  • J Med Chem. 2023 Nov 20. doi: 10.1021/acs.jmedchem.3c01374.
Ying-Zhe Wang  1  2 ,  Hong-Yu Li  1  2 ,  Yan Zhang  1  2 ,  Rui-Xin Jiang  1  2 ,  Jun Xu  2 ,  Jing Gu  2 ,  Zheng Jiang  1  2 ,  Zheng-Yu Jiang  1  2 ,  Qi-Dong You  1  2 ,  Xiao-Ke Guo  1  2
Affiliations
  • 1. State Key Laboratory of Natural Medicines, and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
  • 2. Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
PMID: 37983486 DOI: 10.1021/acs.jmedchem.3c01374
Abstract

M6A (N6-methyladenosine) plays a significant role in regulating RNA processing, splicing, nucleation, translation, and stability. AlkB homologue 5 (ALKBH5) is an Fe(II)/2-oxoglutarate (2-OG)-dependent dioxygenase that demethylates mono- or dimethylated adenosines. ALKBH5 can be regarded as an oncogenic factor for various human cancers. However, the discovery of potent and selective ALKBH5 inhibitors remains a challenge. We identified DDO-2728 as a novel and selective inhibitor of ALKBH5 by structure-based virtual screening and optimization. DDO-2728 was not a 2-oxoglutarate analogue and could selectively inhibit the demethylase activity of ALKBH5 over FTO. DDO-2728 increased the abundance of m6A modifications in AML cells, reduced the mRNA stability of TACC3, and inhibited cell cycle progression. Furthermore, DDO-2728 significantly suppressed tumor growth in the MV4-11 xenograft mouse model and showed a favorable safety profile. Collectively, our results highlight the development of a selective probe for ALKBH5 that will pave the way for the further study of ALKBH5 targeting therapies.

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