Advances in inhibition of protein-protein interactions targeting hypoxia-inducible factor-1 for cancer therapy

• Published in: Bioorganic & medicinal chemistry 2019-04, Vol.27 (7), p.1145-1158
• Main Authors: Li, Jia, Xi, Wanlin, Li, Xiaofang, Sun, Haiying, Li, Yuyan
• Format: Article
• Language: English
• Subjects: Cancer therapy; Cell Hypoxia - drug effects; HIF-1; HIF-1α/HIF-1β hetero-dimerization; HIF-1α/p300; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Models, Molecular; Molecular Conformation; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; PPIs; Protein Binding - drug effects; Small molecular inhibitors; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2019.01.042

[Display omitted] •Critical roles of hypoxia-inducible factor-1 in hypoxia environment.•Two important protein-protein interactions in HIF-1 pathways.•Recent small molecular compounds in inhibition of HIF-1α/HIF-1β dimerization.•Recent small molecular compounds in inhibition of HIF-1α/p300 interaction.•Structure-activity relationships of the reported compounds. Hypoxia is a common characteristic of many types of solid tumors and is associated with tumor propagation, malignant progression, and resistance to anti-cancer therapy. HIF-1 pathway is one of the survival pathways activated in tumor in response to hypoxia. In hypoxic condition, hypoxia-inducible factor-1α (HIF-1α) is stabilized and translocated into nucleus where it forms heterodimer with HIF-1β and regulates the expression of a plethora of genes involved in different processes, such as cell proliferation, differentiation, apoptosis, vascularization/angiogenesis, tumor invasion and metastasis. Recruitment of co-activator p300 or CBP to HIF-1α is critical to the transactivation activity of HIF-1 dimer, therefore, small molecules which can block the dimerization of HIF-1α and HIF-1β or inhibit the interaction between HIF-1α and p300 can function as inhibitors of HIF-1 and have the potential to be developed as novel therapies for the treatment of human cancers. In this review, recent progress of small molecular inhibitors of protein-protein interactions targeting HIF-1 is summarized, the mechanism of functions of these compounds and their potential usage as anti-cancer agents have also been discussed.