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
  • 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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