Group-based optimization of potent and cell-active inhibitors of the von Hippel-Lindau (VHL) E3 ubiquitin ligase: structure-activity relationships leading to the chemical probe (2S,4R)-1-((S)-2-(1-cyanocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (VH298)

Pedro Soares, Morgan Gadd, Julianty Frost, Carles Galdeano, Lucy Ellis, Rafiu Epemolu, Sonia Rocha, Kevin Read, Alessio Ciulli (Lead / Corresponding author)

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Abstract

The von Hippel–Lindau tumor suppressor protein is the substrate binding subunit of the VHL E3 ubiquitin ligase, which targets hydroxylated α subunit of hypoxia inducible factors (HIFs) for ubiquitination and subsequent proteasomal degradation. VHL is a potential target for treating anemia and ischemic diseases, motivating the development of inhibitors of the VHL:HIF-α protein-protein interaction. Additionally, bifunctional proteolysis targeting chimeras (PROTACs) containing a VHL ligand can hijack the E3 ligase activity to induce degradation of target proteins. We report the structure-guided design and group-based optimization of a series of VHL inhibitors with low nanomolar potencies and improved cellular permeability. Structure-activity relationships led to the discovery of potent inhibitors 10 and chemical probe VH298, with dissociation constants <100 nM, which induced marked HIF-1α intracellular stabilization. Our study provides new chemical tools to probe the VHL-HIF pathways, and new VHL ligands for next-generation PROTACs.
Original languageEnglish
Pages (from-to)599-618
Number of pages19
JournalJournal of Medicinal Chemistry
Volume61
Early online date30 Aug 2017
DOIs
Publication statusPublished - 2018

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Ubiquitin-Protein Ligases
Structure-Activity Relationship
Proteolysis
Ligands
Tumor Suppressor Proteins
Hypoxia-Inducible Factor 1
Ubiquitination
Anemia
Permeability
Proteins
pyrrolidine
Hypoxia

Cite this

@article{c4814971e7d746318ad3a0c1be9bf330,
title = "Group-based optimization of potent and cell-active inhibitors of the von Hippel-Lindau (VHL) E3 ubiquitin ligase: structure-activity relationships leading to the chemical probe (2S,4R)-1-((S)-2-(1-cyanocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (VH298)",
abstract = "The von Hippel–Lindau tumor suppressor protein is the substrate binding subunit of the VHL E3 ubiquitin ligase, which targets hydroxylated α subunit of hypoxia inducible factors (HIFs) for ubiquitination and subsequent proteasomal degradation. VHL is a potential target for treating anemia and ischemic diseases, motivating the development of inhibitors of the VHL:HIF-α protein-protein interaction. Additionally, bifunctional proteolysis targeting chimeras (PROTACs) containing a VHL ligand can hijack the E3 ligase activity to induce degradation of target proteins. We report the structure-guided design and group-based optimization of a series of VHL inhibitors with low nanomolar potencies and improved cellular permeability. Structure-activity relationships led to the discovery of potent inhibitors 10 and chemical probe VH298, with dissociation constants <100 nM, which induced marked HIF-1α intracellular stabilization. Our study provides new chemical tools to probe the VHL-HIF pathways, and new VHL ligands for next-generation PROTACs.",
author = "Pedro Soares and Morgan Gadd and Julianty Frost and Carles Galdeano and Lucy Ellis and Rafiu Epemolu and Sonia Rocha and Kevin Read and Alessio Ciulli",
note = "This work was supported by the European Research Council ERC-2012-StG-311460 DrugE3CRLs (Starting Grant to A.C.), the UK Biotechnology and Biological Sciences Research Council BBSRC BB/G023123/2 (David Phillips Fellowship to A.C.), the European Commission PIEF-GA-2012-328030 (Marie-Curie Intra-European Fellowship to C.G.), the Wellcome Trust (PhD Studentship 102398/Z/13/Z to J.F., and strategic awards 100476/Z/12/Z for biophysics and drug discovery and 094090/Z/10/Z for structural biology and X-ray crystallography to BCDD) and the Funda{\cc}{\~a}o para a Ci{\^e}ncia e Tecnologia FCT SFRH/BD/101598/2014 (PhD Studentship to P.S.). S.R. is funded by a Cancer Research UK Senior fellowship C99667/A12918 with support of a Wellcome Trust strategic award 097945/B/11/Z.",
year = "2018",
doi = "10.1021/acs.jmedchem.7b00675",
language = "English",
volume = "61",
pages = "599--618",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",

}

TY - JOUR

T1 - Group-based optimization of potent and cell-active inhibitors of the von Hippel-Lindau (VHL) E3 ubiquitin ligase

T2 - structure-activity relationships leading to the chemical probe (2S,4R)-1-((S)-2-(1-cyanocyclopropanecarboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (VH298)

AU - Soares, Pedro

AU - Gadd, Morgan

AU - Frost, Julianty

AU - Galdeano, Carles

AU - Ellis, Lucy

AU - Epemolu, Rafiu

AU - Rocha, Sonia

AU - Read, Kevin

AU - Ciulli, Alessio

N1 - This work was supported by the European Research Council ERC-2012-StG-311460 DrugE3CRLs (Starting Grant to A.C.), the UK Biotechnology and Biological Sciences Research Council BBSRC BB/G023123/2 (David Phillips Fellowship to A.C.), the European Commission PIEF-GA-2012-328030 (Marie-Curie Intra-European Fellowship to C.G.), the Wellcome Trust (PhD Studentship 102398/Z/13/Z to J.F., and strategic awards 100476/Z/12/Z for biophysics and drug discovery and 094090/Z/10/Z for structural biology and X-ray crystallography to BCDD) and the Fundação para a Ciência e Tecnologia FCT SFRH/BD/101598/2014 (PhD Studentship to P.S.). S.R. is funded by a Cancer Research UK Senior fellowship C99667/A12918 with support of a Wellcome Trust strategic award 097945/B/11/Z.

PY - 2018

Y1 - 2018

N2 - The von Hippel–Lindau tumor suppressor protein is the substrate binding subunit of the VHL E3 ubiquitin ligase, which targets hydroxylated α subunit of hypoxia inducible factors (HIFs) for ubiquitination and subsequent proteasomal degradation. VHL is a potential target for treating anemia and ischemic diseases, motivating the development of inhibitors of the VHL:HIF-α protein-protein interaction. Additionally, bifunctional proteolysis targeting chimeras (PROTACs) containing a VHL ligand can hijack the E3 ligase activity to induce degradation of target proteins. We report the structure-guided design and group-based optimization of a series of VHL inhibitors with low nanomolar potencies and improved cellular permeability. Structure-activity relationships led to the discovery of potent inhibitors 10 and chemical probe VH298, with dissociation constants <100 nM, which induced marked HIF-1α intracellular stabilization. Our study provides new chemical tools to probe the VHL-HIF pathways, and new VHL ligands for next-generation PROTACs.

AB - The von Hippel–Lindau tumor suppressor protein is the substrate binding subunit of the VHL E3 ubiquitin ligase, which targets hydroxylated α subunit of hypoxia inducible factors (HIFs) for ubiquitination and subsequent proteasomal degradation. VHL is a potential target for treating anemia and ischemic diseases, motivating the development of inhibitors of the VHL:HIF-α protein-protein interaction. Additionally, bifunctional proteolysis targeting chimeras (PROTACs) containing a VHL ligand can hijack the E3 ligase activity to induce degradation of target proteins. We report the structure-guided design and group-based optimization of a series of VHL inhibitors with low nanomolar potencies and improved cellular permeability. Structure-activity relationships led to the discovery of potent inhibitors 10 and chemical probe VH298, with dissociation constants <100 nM, which induced marked HIF-1α intracellular stabilization. Our study provides new chemical tools to probe the VHL-HIF pathways, and new VHL ligands for next-generation PROTACs.

U2 - 10.1021/acs.jmedchem.7b00675

DO - 10.1021/acs.jmedchem.7b00675

M3 - Article

C2 - 28853884

VL - 61

SP - 599

EP - 618

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

ER -