DW71177: A novel [1,2,4]triazolo[4,3-a]quinoxaline-based potent and BD1-Selective BET inhibitor for the treatment of acute myeloid leukemia

Imran Ali, Hyung Jin Cha, Byungho Lim, Chong Hak Chae, Jihyun Youm, Whui Jung Park, Sang Ho Lee, Jung Hwan Kim, Docgyun Jeong, Jae Kyung Lim, Yun Ha Hwang, Jae Seok Roe, Jae Sung Woo, Kwangho Lee, Gildon Choi

Research output: Contribution to journalArticlepeer-review

Abstract

The bromodomain and extraterminal domain (BET) family proteins recognize acetyl-lysine (Kac) at the histone tail through two tandem bromodomains, i.e., BD1 and BD2, to regulate gene expression. BET proteins are attractive therapeutic targets in cancer due to their involvement in oncogenic transcriptional activation, and bromodomains have defined Kac-binding pockets. Here, we present DW-71177, a potent BET inhibitor that selectively interacts with BD1 and exhibits strong antileukemic activity. X-ray crystallography, isothermal titration calorimetry, and molecular dynamic studies have revealed the robust and specific binding of DW-71177 to the Kac-binding pocket of BD1. DW-71177 effectively inhibits oncogenes comparable to the pan-BET inhibitor OTX-015, but with a milder impact on housekeeping genes. It efficiently blocks cancer-associated transcriptional changes by targeting genes that are highly enriched with BRD4 and histone acetylation marks, suggesting that BD1-selective targeting could be an effective and safe therapeutic strategy against leukemia.

Original languageEnglish
Article number116052
JournalEuropean Journal of Medicinal Chemistry
Volume265
DOIs
Publication statusPublished - 2024 Feb 5

Bibliographical note

Publisher Copyright:
© 2023 The Authors

Keywords

  • BD1 selectivity
  • BET bromodomain
  • Drug design
  • Epigenetics
  • Leukemia

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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