Design, synthesis, and target identification of new hypoxia-inducible factor 1 (HIF-1) inhibitors containing 1-alkyl-1H-pyrazole-3-carboxamide moiety

Marina Sakai; Nobuaki Takahashi; Hiroaki Ikeda; Yutaka Furutani; Shoko Higuchi; Takehiro Suzuki; Naoshi Dohmae; Sayaka Kobayashi; Hiroshi Harada; Soichi Kojima; Tomokazu Matsuura; Akira Hattori; Hideaki Kakeya

doi:10.1016/j.bmc.2021.116375

Design, synthesis, and target identification of new hypoxia-inducible factor 1 (HIF-1) inhibitors containing 1-alkyl-1H-pyrazole-3-carboxamide moiety

Bioorg Med Chem. 2021 Sep 15:46:116375. doi: 10.1016/j.bmc.2021.116375. Epub 2021 Aug 30.

Affiliations

¹ Department of System Chemotherapy and Molecular Sciences, Division of Bioinformatics and Chemical Genomics, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
² Liver Cancer Prevention Research Unit, RIKEN Cluster for Pioneering Research, Wako, Saitama 351-0198, Japan.
³ Biomolecular Characterization Unit, RIKEN Center for Sustainable Resource Science, Wako, Saitama 351-0198, Japan.
⁴ Laboratory of Cancer Cell Biology, Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan.
⁵ Liver Cancer Prevention Research Unit, RIKEN Cluster for Pioneering Research, Wako, Saitama 351-0198, Japan; Department of Laboratory Medicine, The Jikei University School of Medicine, Tokyo 105-8471, Japan.
⁶ Department of System Chemotherapy and Molecular Sciences, Division of Bioinformatics and Chemical Genomics, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan. Electronic address: scseigyo-hisyo@pharm.kyoto-u.ac.jp.

PMID: 34492592
DOI: 10.1016/j.bmc.2021.116375

Abstract

Hypoxia-inducible factor 1 (HIF-1) is a promising drug target for cancer chemotherapy. In our screening program aimed at identifying new HIF-1 inhibitors by using a hypoxia-responsive luciferase reporter gene assay, KUSC-5001 containing the 1-alkyl-1H-pyrazole-3-carboxamide moiety was found as a potential hit molecule. During an extensive structure-activity relationship (SAR) study, we developed a more effective HIF-1 inhibitor KUSC-5037 (IC₅₀ = 1.2 μM). Under hypoxic conditions, KUSC-5037 suppressed the HIF-1α (a regulatory subunit of HIF-1) mRNA, causing decreases in the gene expression of HIF-1 target genes such as carbonic anhydrase 9 (CA9) and vascular endothelial growth factor (VEGF) genes. Furthermore, by applying our fluorescent and bifunctional probes, ATP5B, a catalytic β subunit of mitochondrial F_oF₁-ATP synthase, was identified as a target protein of KUSC-5037. These results indicate that the derivatives of KUSC-5037 containing the 1-alkyl-1H-pyrazole-3-carboxamide moiety are promising lead molecules for the inhibition of HIF-1 signaling via F_oF₁-ATP synthase suppression.

Keywords: Cancer; Chemotherapy; Hypoxia-inducible factor (HIF); Structure–activity relationship; Target identification.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antigens, Neoplasm / genetics
Antigens, Neoplasm / metabolism
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Carbonic Anhydrase IX / antagonists & inhibitors
Carbonic Anhydrase IX / genetics
Carbonic Anhydrase IX / metabolism
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Female
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors*
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
Molecular Structure
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Structure-Activity Relationship
Vascular Endothelial Growth Factor A / antagonists & inhibitors
Vascular Endothelial Growth Factor A / genetics
Vascular Endothelial Growth Factor A / metabolism

Substances

Antigens, Neoplasm
Antineoplastic Agents
HIF1A protein, human
Hypoxia-Inducible Factor 1, alpha Subunit
Pyrazoles
VEGFA protein, human
Vascular Endothelial Growth Factor A
CA9 protein, human
Carbonic Anhydrase IX