2. Academic Validation
  3. Design, synthesis, and structure-activity relationships of 1-ethylpyrazole-3-carboxamide compounds as novel hypoxia-inducible factor (HIF)-1 inhibitors

Design, synthesis, and structure-activity relationships of 1-ethylpyrazole-3-carboxamide compounds as novel hypoxia-inducible factor (HIF)-1 inhibitors

  • Bioorg Med Chem. 2015 Apr 15;23(8):1776-87. doi: 10.1016/j.bmc.2015.02.038.
Yorinobu Yasuda 1,  Takeaki Arakawa 1,  Yumi Nawata 1,  Sayaka Shimada 1,  Shinya Oishi 2,  Nobutaka Fujii 2,  Shinichi Nishimura 1,  Akira Hattori 1,  Hideaki Kakeya 3
Affiliations

Affiliations

  • 1 Department of System Chemotherapy and Molecular Sciences, Division of Bioinformatics and Chemical Genomics, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
  • 2 Department of Bioorganic Medicinal Chemistry & Chemogenomics, Division of Bioinformatics and Chemical Genomics, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
  • 3 Department of System Chemotherapy and Molecular Sciences, Division of Bioinformatics and Chemical Genomics, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: scseigyo-hisyo@pharm.kyoto-u.ac.jp.
PMID: 25773014 DOI: 10.1016/j.bmc.2015.02.038
Abstract

Hypoxia-inducible factor (HIF)-1 is well known as a promising target for Cancer chemotherapy. By screening an in-house chemical library using a hypoxia-responsive luciferase reporter gene assay, we identified CLB-016 (1) containing 1-ethylpyrazole-3-carboxamide as a HIF-1 inhibitor (IC50=19.1μM). In a subsequent extensive structure-activity relationship (SAR) study, we developed compound 11Ae with an IC50 value of 8.1μM against HIF-1-driven luciferase activity. Compounds 1 and 11Ae were shown to significantly suppress the HIF-1-mediated hypoxia response, including Carbonic Anhydrase IX (CAIX) gene expression and migration of human sarcoma HT1080 cells. These results revealed 1-ethylpyrazole-3-carboxamide as a novel scaffold to develop promising anti-cancer drugs targeting the HIF-1 signaling pathway.

Keywords

Cancer; Chemotherapy; Hypoxia-inducible factor (HIF); Structure–activity relationship.

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