Discovery of DS79540454 via fragment-based drug discovery strategy: New scaffolds of hypoxia-inducible factor prolyl hydroxylase inhibitor

  • Bioorg Med Chem Lett. 2026 Feb 1:131:130476. doi: 10.1016/j.bmcl.2025.130476.
Takeshi Fukuda  1 ,  Tatsuya Nishi  2 ,  Takashi Ishiyama  2 ,  Ryoko Kitazawa  2 ,  Ken Ishii  2 ,  Shinichi Takahashi  2 ,  Yuki Kawabata  2 ,  Kyoji Yamaguchi  2 ,  Daichi Baba  2 ,  Shuichiro Ito  2 ,  Naoki Tanaka  2
Affiliations
  • 1. R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: [email protected].
  • 2. R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
PMID: 41265580 DOI: 10.1016/j.bmcl.2025.130476
Abstract

The inhibition of hypoxia-inducible factor prolyl hydroxylase domain proteins (HIF-PHDs) represents a promising strategy for treating renal anemia. We identified a hydroxypyrimidine core with HIF-PHD inhibitory activity based on a fragment-based drug discovery strategy using various X-ray crystal structures of the HIF-PHD2 domain in complex with a compound. We discovered brand-new amino succinic acid scaffolds by combining the structural information on the crystal structure complexed with 6-acetamide nicotinic acid. DS79540454 exhibits high enzyme inhibitory activity equivalent to that of DS-1093a, which has advanced to clinical trials.

Keywords
Fragment-based drug discovery (FBDD); Hypoxia-inducible factor (HIF); Hypoxia-inducible factor prolyl hydroxylase domain protein (HIF-PHD).
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