2. Academic Validation
  3. Design and Synthesis of Inhibitors of the E3 Ligase SMAD Specific E3 Ubiquitin Protein Ligase 1 as a Treatment for Lung Remodeling in Pulmonary Arterial Hypertension

Design and Synthesis of Inhibitors of the E3 Ligase SMAD Specific E3 Ubiquitin Protein Ligase 1 as a Treatment for Lung Remodeling in Pulmonary Arterial Hypertension

  • J Med Chem. 2023 Jun 22;66(12):8130-8139. doi: 10.1021/acs.jmedchem.3c00229.
Duncan E Shaw 1,  Nichola Smith 1,  Rene Beerli 2,  Simona Cotesta 2,  Pier-Luca D'Alessandro 2,  Anne-Marie Edwards 3,  Rene Lattmann 2,  Dimitrios Lizos 2,  Robert Pulz 2,  Lisa Rooney 3,  Bindi Sohal 3,  Caroline Rynn 2,  Jessica Taylor 3,  Thomas Troxler 2,  Gareth Williams 2,  Sabine Guth 2,  David Rowlands 1
Affiliations

Affiliations

  • 1 Novartis Institutes of Biomedical Research (NIBR), 250 Massachusetts Avenue, Cambridge Massachusetts 01239, United States.
  • 2 NIBR Basel Fabrikstrasse 2, 4056 Basel, Switzerland.
  • 3 NIBR, Wimblehurst Road, Horsham West Sussex RH12 5AB, U.K.
PMID: 37294287 DOI: 10.1021/acs.jmedchem.3c00229
Abstract

Pulmonary arterial hypertension (PAH) is a devastating rare disease, which despite currently available treatments, still represents a high unmet medical need. Specific E3 ubiquitin protein Ligase 1 (SMURF1) is a HECT E3 Ligase that ubiquitinates key signaling molecules from the TGFβ/BMP pathways, which are of great relevance in the pathophysiology of PAH. Herein, the design and synthesis of novel potent small-molecule SMURF1 Ligase inhibitors are described. Lead molecule 38 has demonstrated good oral pharmacokinetics in rats and significant efficacy in a rodent model of pulmonary hypertension.

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