2. Academic Validation
  3. 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

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

  • Eur J Med Chem. 2023 Dec 16:265:116052. doi: 10.1016/j.ejmech.2023.116052.
Imran Ali 1,  Hyung Jin Cha 2,  Byungho Lim 3,  Chong Hak Chae 3,  Jihyun Youm 4,  Whui Jung Park 4,  Sang Ho Lee 4,  Jung Hwan Kim 4,  Docgyun Jeong 4,  Jae Kyung Lim 4,  Yun-Ha Hwang 4,  Jae-Seok Roe 5,  Jae-Sung Woo 6,  Kwangho Lee 7,  Gildon Choi 8
Affiliations

Affiliations

  • 1 Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, Korea National University of Science and Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon 34113, Republic of Korea.
  • 2 Department of Life Sciences, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea.
  • 3 Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Republic of Korea.
  • 4 Dongwha Pharm Research Institute, 71 Tapsil-ro, 35 Beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do 17084, Republic of Korea.
  • 5 Department of Biochemistry, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea.
  • 6 Department of Life Sciences, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea. Electronic address: [email protected].
  • 7 Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, Korea National University of Science and Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon 34113, Republic of Korea. Electronic address: [email protected].
  • 8 Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, Korea National University of Science and Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon 34113, Republic of Korea. Electronic address: [email protected].
PMID: 38134745 DOI: 10.1016/j.ejmech.2023.116052
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.

Keywords

BD1 selectivity; BET bromodomain; Drug design; Epigenetics; Leukemia.

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