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),Journal of Medicinal Chemistry

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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)
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2017-09-18 00:00:00 , DOI: 10.1021/acs.jmedchem.7b00675
Pedro Soares ₁ , Morgan S. Gadd ₁ , Julianty Frost _{1,

2} , Carles Galdeano ₁ , Lucy Ellis ₁ , Ola Epemolu ₁ , Sonia Rocha ₂ , Kevin D. Read ₁ , Alessio Ciulli ₁

Affiliation

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.

中文翻译：

基于组的von Hippel-Lindau（VHL）E3泛素连接酶有效和细胞活性抑制剂的优化：结构-活性关系导致化学探针（2 S，4 R）-1-（（S）-2- （1-氰基环丙烷甲酰胺基）-3,3-二甲基丁酰基）-4-羟基-N-（4-（4-甲基噻唑-5-基）苄基）吡咯烷-2-羧酰胺（VH298）

von Hippel–Lindau肿瘤抑制蛋白是VHL E3泛素连接酶的底物结合亚基，其靶向缺氧诱导因子（HIFs）的羟基化α亚基进行泛素化和随后的蛋白酶体降解。VHL是治疗贫血和缺血性疾病的潜在靶标，从而促进了VHL：HIF-α蛋白与蛋白相互作用抑制剂的发展。此外，包含VHL配体的靶向双功能蛋白水解嵌合体（PROTAC）可以劫持E3连接酶活性，从而诱导目标蛋白降解。我们报告了一系列具有低纳摩尔浓度和改善的细胞渗透性的VHL抑制剂的结构指导设计和基于基团的优化。结构-活性关系导致发现有效的抑制剂10化学探针VH298，解离常数<100 nM，可诱导明显的HIF-1α细胞内稳定。我们的研究提供了新的化学工具，可探测下一代PROTAC的VHL-HIF途径和新的VHL配体。

更新日期：2017-09-18

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