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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).

Soares P, Gadd MS, Frost J, Galdeano C, Ellis L, Epemolu O, Rocha S, Read KD, Ciulli A
J Med Chem 61 599-618 (2018)
Related entries: 5nvv, 5nvw, 5nvx, 5nvy, 5nvz, 5nw1, 5nw2

Cited: 55 times
EuropePMC logo PMID: 28853884

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.

Articles - 5nw0 mentioned but not cited (1)

  1. 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). Soares P, Gadd MS, Frost J, Galdeano C, Ellis L, Epemolu O, Rocha S, Read KD, Ciulli A. J Med Chem 61 599-618 (2018)


Reviews citing this publication (23)

  1. PROteolysis TArgeting Chimeras (PROTACs) - Past, present and future. Pettersson M, Crews CM. Drug Discov Today Technol 31 15-27 (2019)
  2. Advancing targeted protein degradation for cancer therapy. Dale B, Cheng M, Park KS, Kaniskan HÜ, Xiong Y, Jin J. Nat Rev Cancer 21 638-654 (2021)
  3. Degradation of proteins by PROTACs and other strategies. Wang Y, Jiang X, Feng F, Liu W, Sun H. Acta Pharm Sin B 10 207-238 (2020)
  4. Molecular recognition of ternary complexes: a new dimension in the structure-guided design of chemical degraders. Hughes SJ, Ciulli A. Essays Biochem 61 505-516 (2017)
  5. E3 Ligase Ligands for PROTACs: How They Were Found and How to Discover New Ones. Ishida T, Ciulli A. SLAS Discov 26 484-502 (2021)
  6. PROTACs- a game-changing technology. Konstantinidou M, Li J, Zhang B, Wang Z, Shaabani S, Ter Brake F, Essa K, Dömling A. Expert Opin Drug Discov 14 1255-1268 (2019)
  7. Proteolysis targeting chimeras (PROTACs) come of age: entering the third decade of targeted protein degradation. Bond MJ, Crews CM. RSC Chem Biol 2 725-742 (2021)
  8. PROTACs: past, present and future. Li K, Crews CM. Chem Soc Rev 51 5214-5236 (2022)
  9. Put a ring on it: application of small aliphatic rings in medicinal chemistry. Bauer MR, Di Fruscia P, Lucas SCC, Michaelides IN, Nelson JE, Storer RI, Whitehurst BC. RSC Med Chem 12 448-471 (2021)
  10. Small Molecule Modulators of RING-Type E3 Ligases: MDM and Cullin Families as Targets. Bulatov E, Zagidullin A, Valiullina A, Sayarova R, Rizvanov A. Front Pharmacol 9 450 (2018)
  11. Proteolysis targeting chimeras (PROTACs) in cancer therapy. Ocaña A, Pandiella A. J Exp Clin Cancer Res 39 189 (2020)
  12. Discovery of small molecule ligands for the von Hippel-Lindau (VHL) E3 ligase and their use as inhibitors and PROTAC degraders. Diehl CJ, Ciulli A. Chem Soc Rev 51 8216-8257 (2022)
  13. Targeting TRIM Proteins: A Quest towards Drugging an Emerging Protein Class. D'Amico F, Mukhopadhyay R, Ovaa H, Mulder MPC. Chembiochem 22 2011-2031 (2021)
  14. Emerging modes-of-action in drug discovery. Valeur E, Narjes F, Ottmann C, Plowright AT. Medchemcomm 10 1550-1568 (2019)
  15. E3 Ubiquitin Ligases: Key Regulators of TGFβ Signaling in Cancer Progression. Sinha A, Iyengar PV, Ten Dijke P. Int J Mol Sci 22 E476 (2021)
  16. Discovery of E3 Ligase Ligands for Target Protein Degradation. Lee J, Lee Y, Jung YM, Park JH, Yoo HS, Park J. Molecules 27 6515 (2022)
  17. Small molecule PROTACs: an emerging technology for targeted therapy in drug discovery. Pei H, Peng Y, Zhao Q, Chen Y. RSC Adv 9 16967-16976 (2019)
  18. LRSAM1 E3 ubiquitin ligase: molecular neurobiological perspectives linked with brain diseases. Mishra R, Upadhyay A, Prajapati VK, Dhiman R, Poluri KM, Jana NR, Mishra A. Cell Mol Life Sci 76 2093-2110 (2019)
  19. Proteasomal Degradation of Zn-Dependent Hdacs: The E3-Ligases Implicated and the Designed Protacs That Enable Degradation. Márquez-Cantudo L, Ramos A, Coderch C, de Pascual-Teresa B. Molecules 26 5606 (2021)
  20. Recent advancements in the discovery of cereblon-based protease-targeted chimeras with potential for therapeutic intervention. Singh H, Agrawal DK. Future Med Chem 14 1403-1416 (2022)
  21. PROTAC'ing oncoproteins: targeted protein degradation for cancer therapy. Kelm JM, Pandey DS, Malin E, Kansou H, Arora S, Kumar R, Gavande NS. Mol Cancer 22 62 (2023)
  22. Function, mechanism and drug discovery of ubiquitin and ubiquitin-like modification with multiomics profiling for cancer therapy. Jiang Y, Ni S, Xiao B, Jia L. Acta Pharm Sin B 13 4341-4372 (2023)
  23. PROTACs: A novel strategy for cancer drug discovery and development. Han X, Sun Y. MedComm (2020) 4 e290 (2023)

Articles citing this publication (31)

  1. BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design. Farnaby W, Koegl M, Roy MJ, Whitworth C, Diers E, Trainor N, Zollman D, Steurer S, Karolyi-Oezguer J, Riedmueller C, Gmaschitz T, Wachter J, Dank C, Galant M, Sharps B, Rumpel K, Traxler E, Gerstberger T, Schnitzer R, Petermann O, Greb P, Weinstabl H, Bader G, Zoephel A, Weiss-Puxbaum A, Ehrenhöfer-Wölfer K, Wöhrle S, Boehmelt G, Rinnenthal J, Arnhof H, Wiechens N, Wu MY, Owen-Hughes T, Ettmayer P, Pearson M, McConnell DB, Ciulli A. Nat Chem Biol 15 672-680 (2019)
  2. Iterative Design and Optimization of Initially Inactive Proteolysis Targeting Chimeras (PROTACs) Identify VZ185 as a Potent, Fast, and Selective von Hippel-Lindau (VHL) Based Dual Degrader Probe of BRD9 and BRD7. Zoppi V, Hughes SJ, Maniaci C, Testa A, Gmaschitz T, Wieshofer C, Koegl M, Riching KM, Daniels DL, Spallarossa A, Ciulli A. J Med Chem 62 699-726 (2019)
  3. Structure-Based Discovery of SD-36 as a Potent, Selective, and Efficacious PROTAC Degrader of STAT3 Protein. Zhou H, Bai L, Xu R, Zhao Y, Chen J, McEachern D, Chinnaswamy K, Wen B, Dai L, Kumar P, Yang CY, Liu Z, Wang M, Liu L, Meagher JL, Yi H, Sun D, Stuckey JA, Wang S. J Med Chem 62 11280-11300 (2019)
  4. 3-Fluoro-4-hydroxyprolines: Synthesis, Conformational Analysis, and Stereoselective Recognition by the VHL E3 Ubiquitin Ligase for Targeted Protein Degradation. Testa A, Lucas X, Castro GV, Chan KH, Wright JE, Runcie AC, Gadd MS, Harrison WTA, Ko EJ, Fletcher D, Ciulli A. J Am Chem Soc 140 9299-9313 (2018)
  5. Cereblon versus VHL: Hijacking E3 ligases against each other using PROTACs. Girardini M, Maniaci C, Hughes SJ, Testa A, Ciulli A. Bioorg Med Chem 27 2466-2479 (2019)
  6. Derivatization of inhibitor of apoptosis protein (IAP) ligands yields improved inducers of estrogen receptor α degradation. Ohoka N, Morita Y, Nagai K, Shimokawa K, Ujikawa O, Fujimori I, Ito M, Hayase Y, Okuhira K, Shibata N, Hattori T, Sameshima T, Sano O, Koyama R, Imaeda Y, Nara H, Cho N, Naito M. J Biol Chem 293 6776-6790 (2018)
  7. PROTAC-mediated crosstalk between E3 ligases. Steinebach C, Kehm H, Lindner S, Vu LP, Köpff S, López Mármol Á, Weiler C, Wagner KG, Reichenzeller M, Krönke J, Gütschow M. Chem Commun (Camb) 55 1821-1824 (2019)
  8. Rapid and Reversible Knockdown of Endogenously Tagged Endosomal Proteins via an Optimized HaloPROTAC Degrader. Tovell H, Testa A, Maniaci C, Zhou H, Prescott AR, Macartney T, Ciulli A, Alessi DR. ACS Chem Biol 14 882-892 (2019)
  9. A small molecule HIF-1α stabilizer that accelerates diabetic wound healing. Li G, Ko CN, Li D, Yang C, Wang W, Yang GJ, Di Primo C, Wong VKW, Xiang Y, Lin L, Ma DL, Leung CH. Nat Commun 12 3363 (2021)
  10. Understanding and Improving the Membrane Permeability of VH032-Based PROTACs. Klein VG, Townsend CE, Testa A, Zengerle M, Maniaci C, Hughes SJ, Chan KH, Ciulli A, Lokey RS. ACS Med Chem Lett 11 1732-1738 (2020)
  11. Amide-to-Ester Substitution as a Strategy for Optimizing PROTAC Permeability and Cellular Activity. Klein VG, Bond AG, Craigon C, Lokey RS, Ciulli A. J Med Chem 64 18082-18101 (2021)
  12. A suite of mathematical solutions to describe ternary complex formation and their application to targeted protein degradation by heterobifunctional ligands. Han B. J Biol Chem 295 15280-15291 (2020)
  13. Non-Coding Micro RNAs and Hypoxia-Inducible Factors Are Selenium Targets for Development of a Mechanism-Based Combination Strategy in Clear-Cell Renal Cell Carcinoma-Bench-to-Bedside Therapy. Rustum YM, Chintala S, Durrani FA, Bhattacharya A. Int J Mol Sci 19 E3378 (2018)
  14. Discovery of XL01126: A Potent, Fast, Cooperative, Selective, Orally Bioavailable, and Blood-Brain Barrier Penetrant PROTAC Degrader of Leucine-Rich Repeat Kinase 2. Liu X, Kalogeropulou AF, Domingos S, Makukhin N, Nirujogi RS, Singh F, Shpiro N, Saalfrank A, Sammler E, Ganley IG, Moreira R, Alessi DR, Ciulli A. J Am Chem Soc 144 16930-16952 (2022)
  15. Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders. Hanzl A, Casement R, Imrichova H, Hughes SJ, Barone E, Testa A, Bauer S, Wright J, Brand M, Ciulli A, Winter GE. Nat Chem Biol 19 323-333 (2023)
  16. Optimization of Class I Histone Deacetylase PROTACs Reveals that HDAC1/2 Degradation is Critical to Induce Apoptosis and Cell Arrest in Cancer Cells. Smalley JP, Baker IM, Pytel WA, Lin LY, Bowman KJ, Schwabe JWR, Cowley SM, Hodgkinson JT. J Med Chem 65 5642-5659 (2022)
  17. Spy vs. spy: selecting the best reporter for 19F NMR competition experiments. de Castro GV, Ciulli A. Chem Commun (Camb) 55 1482-1485 (2019)
  18. Development of BromoTag: A "Bump-and-Hole"-PROTAC System to Induce Potent, Rapid, and Selective Degradation of Tagged Target Proteins. Bond AG, Craigon C, Chan KH, Testa A, Karapetsas A, Fasimoye R, Macartney T, Blow JJ, Alessi DR, Ciulli A. J Med Chem 64 15477-15502 (2021)
  19. Mechanistic and Structural Features of PROTAC Ternary Complexes. Casement R, Bond A, Craigon C, Ciulli A. Methods Mol Biol 2365 79-113 (2021)
  20. RNA-seq analysis of PHD and VHL inhibitors reveals differences and similarities to the hypoxia response. Frost J, Ciulli A, Rocha S. Wellcome Open Res 4 17 (2019)
  21. microRNA-222-Mediated VHL Downregulation Facilitates Retinoblastoma Chemoresistance by Increasing HIF1α Expression. Li C, Zhao J, Sun W. Invest Ophthalmol Vis Sci 61 9 (2020)
  22. Von Hippel-Lindau (VHL) small-molecule inhibitor binding increases stability and intracellular levels of VHL protein. Frost J, Rocha S, Ciulli A. J Biol Chem 297 100910 (2021)
  23. Thioamide substitution to probe the hydroxyproline recognition of VHL ligands. Soares P, Lucas X, Ciulli A. Bioorg Med Chem 26 2992-2995 (2018)
  24. A High-Throughput Method to Prioritize PROTAC Intracellular Target Engagement and Cell Permeability Using NanoBRET. Vasta JD, Corona CR, Robers MB. Methods Mol Biol 2365 265-282 (2021)
  25. DeepPROTACs is a deep learning-based targeted degradation predictor for PROTACs. Li F, Hu Q, Zhang X, Sun R, Liu Z, Wu S, Tian S, Ma X, Dai Z, Yang X, Gao S, Bai F. Nat Commun 13 7133 (2022)
  26. Development of BODIPY FL VH032 as a High-Affinity and Selective von Hippel-Lindau E3 Ligase Fluorescent Probe and Its Application in a Time-Resolved Fluorescence Resonance Energy-Transfer Assay. Lin W, Li Y, Yang L, Chen T. ACS Omega 6 680-695 (2021)
  27. Identification and Characterization of a Novel Indoleamine 2,3-Dioxygenase 1 Protein Degrader for Glioblastoma. Bollu LR, Bommi PV, Monsen PJ, Zhai L, Lauing KL, Bell A, Kim M, Ladomersky E, Yang X, Platanias LC, Matei DE, Bonini MG, Munshi HG, Hashizume R, Wu JD, Zhang B, James CD, Chen P, Kocherginsky M, Horbinski C, Cameron MD, Grigorescu AA, Yamini B, Lukas RV, Schiltz GE, Wainwright DA. J Med Chem 65 15642-15662 (2022)
  28. Discovery of a First-in-Class Degrader for the Lipid Kinase PIKfyve. Li C, Qiao Y, Jiang X, Liu L, Zheng Y, Qiu Y, Cheng C, Zhou F, Zhou Y, Huang W, Ren X, Wang Y, Wang Z, Chinnaiyan AM, Ding K. J Med Chem 66 12432-12445 (2023)
  29. Small Molecule Degraders of Protein Tyrosine Phosphatase 1B and T-Cell Protein Tyrosine Phosphatase for Cancer Immunotherapy. Dong J, Miao J, Miao Y, Qu Z, Zhang S, Zhu P, Wiede F, Jassim BA, Bai Y, Nguyen Q, Lin J, Chen L, Tiganis T, Tao WA, Zhang ZY. Angew Chem Int Ed Engl 62 e202303818 (2023)
  30. 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-1α Stabilizers. Vu LP, Diehl CJ, Casement R, Bond AG, Steinebach C, Strašek N, Bricelj A, Perdih A, Schnakenburg G, Sosič I, Ciulli A, Gütschow M. J Med Chem 66 12776-12811 (2023)
  31. Structure-based design of a phosphotyrosine-masked covalent ligand targeting the E3 ligase SOCS2. Ramachandran S, Makukhin N, Haubrich K, Nagala M, Forrester B, Lynch DM, Casement R, Testa A, Bruno E, Gitto R, Ciulli A. Nat Commun 14 6345 (2023)


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