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

Carles Galdeano; Morgan S. Gadd; Pedro Soares; Salvatore Scaffidi; Inge Van Molle; Ipek Birced; Sarah Hewitt; David M. Dias; Alessio Ciulli

doi:10.1021/jm5011258

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

Carles Galdeano , Morgan S. Gadd, Pedro Soares, Salvatore Scaffidi, Inge Van Molle, Ipek Birced, Sarah Hewitt, David M. Dias, Alessio Ciulli (Lead / Corresponding author)

Research output: Contribution to journal › Article › peer-review

282 Citations (Scopus)

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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.

Original language	English
Pages (from-to)	8657-8663
Number of pages	7
Journal	Journal of Medicinal Chemistry
Volume	57
Issue number	20
DOIs	https://doi.org/10.1021/jm5011258
Publication status	Published - 23 Oct 2014

Keywords

Crystallography, X-Ray
Humans
Hypoxia-Inducible Factor 1, alpha Subunit
Ligands
Models, Molecular
Molecular Targeted Therapy
Protein Binding
Small Molecule Libraries
Structure-Activity Relationship
Von Hippel-Lindau Tumor Suppressor Protein

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/jm5011258

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DrugE3CRL's: Probing Druggability of Multisubunit Complexes: E3 Cullin RING Ligases (ERC Starting Grant)
Ciulli, A. (Investigator)
COMMISSION OF THE EUROPEAN COMMUNITIES
1/05/13 → 30/04/18
Project: Research
Dissecting and Exploiting Molecular Recognition at Protein-Protein Interfaces (David Phillips Fellowship)
Ciulli, A. (Investigator)
Biotechnology and Biological Sciences Research Council
8/04/13 → 7/07/15
Project: Research
Design of Orthogonal Molecular Probes Targeting Engineered Von-Hippel Lindau (VHL) E3 Ubiquitin Ligase for the Control of Intercellular Protein Levels
Ciulli, A. (Investigator)
COMMISSION OF THE EUROPEAN COMMUNITIES
8/04/13 → 7/04/15
Project: Research

Ciulli, Alessio
- Centre for Targeted Protein Degradation - Professor of Chemical and Structural Biology
Person: Academic

Cite this

Galdeano , C., Gadd, M. S., Soares, P., Scaffidi, S., Van Molle, I., Birced, I., Hewitt, S., Dias, D. M., & Ciulli, A. (2014). 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. Journal of Medicinal Chemistry, 57(20), 8657-8663. https://doi.org/10.1021/jm5011258

Galdeano , Carles ; Gadd, Morgan S. ; Soares, Pedro et al. / 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. In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 20. pp. 8657-8663.

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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.",

keywords = "Crystallography, X-Ray, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Ligands, Models, Molecular, Molecular Targeted Therapy, Protein Binding, Small Molecule Libraries, Structure-Activity Relationship, Von Hippel-Lindau Tumor Suppressor Protein",

author = "Carles Galdeano and Gadd, {Morgan S.} and Pedro Soares and Salvatore Scaffidi and {Van Molle}, Inge and Ipek Birced and Sarah Hewitt and Dias, {David M.} and Alessio Ciulli",

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doi = "10.1021/jm5011258",

language = "English",

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Galdeano , C, Gadd, MS, Soares, P, Scaffidi, S, Van Molle, I, Birced, I, Hewitt, S, Dias, DM & Ciulli, A 2014, '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', Journal of Medicinal Chemistry, vol. 57, no. 20, pp. 8657-8663. https://doi.org/10.1021/jm5011258

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. / Galdeano , Carles; Gadd, Morgan S.; Soares, Pedro et al.
In: Journal of Medicinal Chemistry, Vol. 57, No. 20, 23.10.2014, p. 8657-8663.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

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AU - Galdeano , Carles

AU - Gadd, Morgan S.

AU - Soares, Pedro

AU - Scaffidi, Salvatore

AU - Van Molle, Inge

AU - Birced, Ipek

AU - Hewitt, Sarah

AU - Dias, David M.

AU - Ciulli, Alessio

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AB - 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.

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KW - Molecular Targeted Therapy

KW - Protein Binding

KW - Small Molecule Libraries

KW - Structure-Activity Relationship

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Galdeano C, Gadd MS, Soares P, Scaffidi S, Van Molle I, Birced I et al. 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. Journal of Medicinal Chemistry. 2014 Oct 23;57(20):8657-8663. doi: 10.1021/jm5011258

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

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Projects

DrugE3CRL's: Probing Druggability of Multisubunit Complexes: E3 Cullin RING Ligases (ERC Starting Grant)

Dissecting and Exploiting Molecular Recognition at Protein-Protein Interfaces (David Phillips Fellowship)

Design of Orthogonal Molecular Probes Targeting Engineered Von-Hippel Lindau (VHL) E3 Ubiquitin Ligase for the Control of Intercellular Protein Levels

Profiles

Ciulli, Alessio

Cite this