Discovery of a potent orally available pyrazolopyridone derivative as a novel selective bromodomain and extra-terminal domain (BET)-first bromodomain (BD1) inhibitor

  • Bioorg Med Chem Lett. 2024 Sep 1:109:129849. doi: 10.1016/j.bmcl.2024.129849.
Shuichi Hagihara  1 ,  Kouhei Ishizawa  2 ,  Kana Soga  3 ,  Takashi Honjo  3 ,  Shigeki Takai  3 ,  Yuko Kawano  3 ,  Manami Kikuchi  3 ,  Akiko Nishidate  3 ,  Fumi Matsumoto  3 ,  Mikako Murase  3 ,  Naohiro Hashimoto  3 ,  Chiduko Sasaki  3 ,  Ikuko Miyaguchi  3 ,  Okimasa Okada  3 ,  Tomoya Akashi  3 ,  Shinji Nakayama  3 ,  Yuko Ogasawara  3 ,  Junichi Endo  3
Affiliations
  • 1. Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan. Electronic address: [email protected].
  • 2. Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan. Electronic address: [email protected].
  • 3. Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama 227-0033, Japan.
PMID: 38876177 DOI: 10.1016/j.bmcl.2024.129849
Abstract

Clinical studies have shown that inhibitors of bromodomain and extra-terminal domain (BET) proteins, particularly BRD4, have antitumor activity and efficacy. The BET protein has two domains, BD1 and BD2, and we previously focused on BD1 and reported orally bioavailable BD1-selective inhibitors. In this study, we obtained a BD1 Inhibitor, a more potent and highly selective pyrazolopyridone derivative 13a, and confirmed its in vivo efficacy.

Keywords
BD1 selectivity; BET family; Inflammation; Pyrazolopyridone; X-ray crystallography.
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