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Potency-Enhanced Peptidomimetic VHL Ligands with Improved Oral Bioavailability.
Wu, Hao; Murray, Jeremy; Ishisoko, Noriko; Frommlet, Alexandra; Deshmukh, Gauri; DiPasquale, Antonio; Mulvihill, Melinda M; Zhang, Donglu; Quinn, John G; Blake, Robert A; Fairbrother, Wayne J; Fuhrmann, Jakob.
Affiliation
  • Wu H; Department of Early Discovery Biochemistry, Genentech, 1 DNA Way, South San Francisco, California 94080, United States.
  • Murray J; Department of Structural Biology, Genentech, 1 DNA Way, South San Francisco, California 94080, United States.
  • Ishisoko N; Department of Biochemical & Cellular Pharmacology, Genentech, 1 DNA Way, South San Francisco, California 94080, United States.
  • Frommlet A; Department of Biochemical & Cellular Pharmacology, Genentech, 1 DNA Way, South San Francisco, California 94080, United States.
  • Deshmukh G; Department of Drug Metabolism and Pharmacokinetics, Genentech, 1 DNA Way, South San Francisco, California 94080, United States.
  • DiPasquale A; Department of Small Molecule Pharmaceutical Sciences, Genentech, 1 DNA Way, South San Francisco, California 94080, United States.
  • Mulvihill MM; Department of Biochemical & Cellular Pharmacology, Genentech, 1 DNA Way, South San Francisco, California 94080, United States.
  • Zhang D; Department of Drug Metabolism and Pharmacokinetics, Genentech, 1 DNA Way, South San Francisco, California 94080, United States.
  • Quinn JG; Department of Biochemical & Cellular Pharmacology, Genentech, 1 DNA Way, South San Francisco, California 94080, United States.
  • Blake RA; Department of Biochemical & Cellular Pharmacology, Genentech, 1 DNA Way, South San Francisco, California 94080, United States.
  • Fairbrother WJ; Department of Early Discovery Biochemistry, Genentech, 1 DNA Way, South San Francisco, California 94080, United States.
  • Fuhrmann J; Department of Early Discovery Biochemistry, Genentech, 1 DNA Way, South San Francisco, California 94080, United States.
J Med Chem ; 67(11): 8585-8608, 2024 Jun 13.
Article in En | MEDLINE | ID: mdl-38809766
ABSTRACT
The von Hippel-Lindau (VHL) protein plays a pivotal role in regulating the hypoxic stress response and has been extensively studied and utilized in the targeted protein degradation field, particularly in the context of bivalent degraders. In this study, we present a comprehensive peptidomimetic structure-activity relationship (SAR) approach, combined with cellular NanoBRET target engagement assays to enhance the existing VHL ligands. Through systematic modifications of the molecule, we identified the 1,2,3-triazole group as an optimal substitute of the left-hand side amide bond that yields 10-fold higher binding activity. Moreover, incorporating conformationally constrained alterations on the methylthiazole benzylamine moiety led to the development of highly potent VHL ligands with picomolar binding affinity and significantly improved oral bioavailability. We anticipate that our optimized VHL ligand, GNE7599, will serve as a valuable tool compound for investigating the VHL pathway and advancing the field of targeted protein degradation.
Subject(s)

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Biological Availability / Von Hippel-Lindau Tumor Suppressor Protein / Peptidomimetics Limits: Animals / Humans Language: En Journal: J Med Chem Journal subject: QUIMICA Year: 2024 Document type: Article Affiliation country: United States

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Biological Availability / Von Hippel-Lindau Tumor Suppressor Protein / Peptidomimetics Limits: Animals / Humans Language: En Journal: J Med Chem Journal subject: QUIMICA Year: 2024 Document type: Article Affiliation country: United States