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Structure-guided design and optimization of small molecules targeting the protein–protein interaction between the von Hippel–Lindau (VHL) E3 ubiquitin ligase and the Hypoxia Inducible Factor (HIF) alpha subunit with in vitro nanomolar affinities
DOI:
10.1021/jm5011258
PMID:
25166285
Authors:
Carles
Galdeano
(University of Dundee)
,
Morgan
Gadd
(University of Dundee)
,
Pedro
Soares
(University of Dundee)
,
Salvatore
Scaffidi
(University of Dundee)
,
Inge
Van Molle
(University of Cambridge)
,
Ipek
Birced
(University of Dundee)
,
Sarah
Hewitt
(University of Cambridge)
,
David M.
Dias
(University of Cambridge)
,
Alessio
Ciulli
(University of Dundee)
Co-authored by industrial partner:
No
Type:
Journal Paper
Journal:
Journal Of Medicinal Chemistry
, VOL 57 (20)
, PAGES 8657 - 8663
State:
Published (Approved)
Published:
October 2014
Diamond Proposal Number(s):
8268

Abstract: E3 ubiquitin ligases are attractive targets in the ubiquitin–proteasome system, however, the development of small-molecule ligands has been rewarded with limited success. The von Hippel–Lindau protein (pVHL) is the substrate recognition subunit of the VHL E3 ligase that targets HIF-1α for degradation. We recently reported inhibitors of the pVHL:HIF-1α interaction, however they exhibited moderate potency. Herein, we report the design and optimization, guided by X-ray crystal structures, of a ligand series with nanomolar binding affinities.
Journal Keywords: Crystal structure; Inhibitors; Ligands; Noncovalent interactions; Peptides and proteins
Subject Areas:
Biology and Bio-materials,
Medicine,
Chemistry
Instruments:
I03-Macromolecular Crystallography
,
I04-Macromolecular Crystallography
Other Facilities: ID14-4, BM14 at ESRF
Added On:
24/02/2015 11:15
Documents:
jm5011258-1.pdf
Discipline Tags:
Health & Wellbeing
Biochemistry
Chemistry
Structural biology
Organic Chemistry
Drug Discovery
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)