8cql | pdb_00008cql
pVHL:EloB:EloC in complex with (2S,4R)-N-((S)-1-(5-Fluoro-2-methoxy-4-(4-methylthiazol-5-yl)phenyl)ethyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide (Compound 33)
Structural highlights
FunctionELOC_HUMAN SIII, also known as elongin, is a general transcription elongation factor that increases the RNA polymerase II transcription elongation past template-encoded arresting sites. Subunit A is transcriptionally active and its transcription activity is strongly enhanced by binding to the dimeric complex of the SIII regulatory subunits B and C (elongin BC complex).[1] The elongin BC complex seems to be involved as an adapter protein in the proteasomal degradation of target proteins via different E3 ubiquitin ligase complexes, including the von Hippel-Lindau ubiquitination complex CBC(VHL). By binding to BC-box motifs it seems to link target recruitment subunits, like VHL and members of the SOCS box family, to Cullin/RBX1 modules that activate E2 ubiquitination enzymes.[2] Publication Abstract from PubMedHypoxia-inducible factor-1alpha (HIF-1alpha) constitutes the principal mediator of cellular adaptation to hypoxia in humans. The HIF-1alpha protein level and activity are tightly regulated by the ubiquitin E3 ligase von Hippel-Lindau (VHL). Here, we performed a structure-guided and bioactivity-driven design of new VHL inhibitors. Our iterative and combinatorial strategy focused on chemical variability at the phenylene unit and encompassed further points of diversity. The exploitation of tailored phenylene fragments and the stereoselective installation of the benzylic methyl group provided potent VHL ligands. Three high-resolution structures of VHL-ligand complexes were determined, and bioactive conformations of these ligands were explored. The most potent inhibitor (30) 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-1alpha transcriptional activity. Our work is anticipated to inspire future efforts toward HIF-1alpha stabilizers and new ligands for proteolysis-targeting chimera (PROTAC) degraders. 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-1alpha Stabilizers.,Vu LP, Diehl CJ, Casement R, Bond AG, Steinebach C, Strasek N, Bricelj A, Perdih A, Schnakenburg G, Sosic I, Ciulli A, Gutschow M J Med Chem. 2023 Sep 14. doi: 10.1021/acs.jmedchem.3c00434. PMID:37708384[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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