Hypoxia inducible factors (HIFs) are transcriptional factors promoting the growth of numerous tumors. These proteins are, therefore, important therapeutic targets. Nevertheless, the development of pharmacological inhibitors is challenging as HIFs lack active sites.
Thomas Scheuermann, University of Texas Southwestern Medical Center, Dallas, USA, circumvented this problem by focusing their attention on a domain present in the α subunit of HIF-2 and known as Per-ARNT-Sim (PAS). This domain guarantees the hetero-dimerization of HIF-2α with its partner HIF-β and the consequent assembly of an active molecule. PAS, moreover, contains a cavity which is accessible to small-molecule ligands. The researchers, thus, screened and optimized chemicals able to bind HIF-2α in its PAS domain. In this way, they obtained the pictured compound. This small molecule antagonizes HIF-2α by inducing allosteric changes which prevent its dimerization and, thus, the formation of an active HIF complex.
- Allosteric inhibition of hypoxia inducible factor-2 with small molecules,
T. H Scheuermann, Q. Li, H. Ma, J. Key, L. Zhang, R. Chen, J. A. Garcia, J. Naidoo, J. Longgood, D. E. Frantz, U. K. Tambar, K. E. Gardner, R. K. Bruick,
Nat. Chem. Biol. 2013.