Expanding the Structural Diversity at the Phenylene Core of Ligands for the von Hippel–Lindau E3 Ubiquitin Ligase: Development of Highly Potent Hypoxia-Inducible Factor-1α Stabilizers
Lan Phuong Vu, Claudia J. Diehl, Ryan Casement, Adam G. Bond, Christian Steinebach, Nika Strašek, Aleša Bricelj, Andrej Perdih, Gregor Schnakenburg, Izidor Sosič, Alessio Ciulli, Michael Gütschow
Abstract
) exhibited dissociation constants lower than 40 nM, independently determined by fluorescence polarization and surface plasmon resonance and an enhanced cellular potency, as evidenced by its superior ability to induce HIF-1α transcriptional activity. Our work is anticipated to inspire future efforts toward HIF-1α stabilizers and new ligands for proteolysis-targeting chimera (PROTAC) degraders.
Topics & Concepts
ChemistryUbiquitinUbiquitin ligaseDNA ligaseHypoxia-inducible factorsProteolysisStereochemistryLigand (biochemistry)Cell biologyStructure–activity relationshipBiophysicsBiochemistryReceptorDNAIn vitroEnzymeGeneBiologyProtein Degradation and InhibitorsUbiquitin and proteasome pathwaysHistone Deacetylase Inhibitors Research