Synthesis and structure–activity relationships of novel, potent, orally active hypoxia-inducible factor-1 inhibitors

• Published in: Bioorganic & medicinal chemistry Vol. 22; no. 19; pp. 5513 - 5529
• Main Authors: Nagao, Satoshi, Yamane, Yoshinobu, Funasaka, Setsuo, Tanaka, Keigo, Miyazaki, Kazuki, Kotake, Yoshihiko, Kamata, Jun-ichi, Watanabe-Miyano, Saori, Toyama, Osamu, Ozawa, Yoichi, Mizui, Yoshiharu, Okamoto, Kiyoshi, Ito, Daisuke
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.10.2014; Elsevier
• Subjects: Anilides - administration & dosage; Anilides - chemical synthesis; Anilides - chemistry; Anilides - pharmacology; Biochemistry & Molecular Biology; Cancer; Cell Line, Tumor; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dose-Response Relationship, Drug; High-Throughput Screening Assays; Humans; Hypoxia; Hypoxia-Inducible Factor 1 - antagonists & inhibitors; Hypoxia-inducible factor-1; Inhibitor; Life Sciences & Biomedicine; Molecular Structure; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; Small molecule; Small Molecule Libraries - administration & dosage; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Structure-Activity Relationship; Structure–activity relationships; MNBA; HTS; DIBAL; PHD; Hypoxia-inducible factor-1; Structure–activity relationships; HIF-1; VEGF-PLAP; Hypoxia; Inhibitor; VHL; Small molecule; NBS; Cancer; TARGET; ACID; HIGHLY POTENT; Structure-activity relationships; ANTAGONISTS; DISCOVERY
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2014.07.020

Hypoxia-inducible factor-1 (HIF-1) is the chief transcription factor regulating hypoxia-driven gene expression. HIF-1 overexpression is associated with poor prognosis in several cancers and therefore represents an attractive target for novel antitumor agents. We explored small molecule inhibitors of the HIF-1 pathway. Using high-throughput-screening, we identified benzanilide compound 1 (IC50=560nM) as a seed. Subsequent extensive derivatization led to the discovery of compounds 43a and 51d, with anti-HIF-1 activities in vitro (IC50=21 and 0.47nM, respectively), and in vivo. Additionally, 43a (12.5–100mg/kg) also displayed in vivo anti-tumor efficacy, without influencing body weight.