Discovery of VU6015929: A Selective Discoidin Domain Receptor 1/2 (DDR1/2) Inhibitor to Explore the Role of DDR1 in Antifibrotic Therapy

  • ACS Med Chem Lett. 2019 Nov 25;11(1):29-33. doi: 10.1021/acsmedchemlett.9b00382.
Daniel E Jeffries  1 ,  Corina M Borza  2 ,  Anna L Blobaum  3  4 ,  Ambra Pozzi  2  5 ,  Craig W Lindsley  1  3  4
Affiliations
  • 1. Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 2. Department of Medicine, Division of Nephrology, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 3. Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 4. Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 5. Veterans Affairs Medical Center, Nashville, Nashville, Tennessee 37232, United States.
PMID: 31938459 DOI: 10.1021/acsmedchemlett.9b00382
Abstract

Herein, we report the discovery of a potent and selective dual DDR1/2 inhibitor, 7e (VU6015929), displaying low cytotoxicity, good kinome selectivity, and possessing an acceptable in vitro DMPK profile with good rodent in vivo pharmacokinetics. VU6015929 potently blocks collagen-induced DDR1 activation and collagen-IV production, suggesting DDR1 inhibition as an exciting target for antifibrotic therapy.