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

Bioorg Med Chem. 2019 Apr 1;27(7):1145-1158. doi: 10.1016/j.bmc.2019.01.042. Epub 2019 Feb 2.


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.

Keywords: Cancer therapy; HIF-1; HIF-1α/HIF-1β hetero-dimerization; HIF-1α/p300; PPIs; Small molecular inhibitors.

Publication types

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

MeSH terms

  • Cell Hypoxia / drug effects*
  • 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
  • Protein Binding / drug effects
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*


  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Small Molecule Libraries