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

Daniel E Jeffries; Corina M Borza; Anna L Blobaum; Ambra Pozzi; Craig W Lindsley

doi:10.1021/acsmedchemlett.9b00382

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. eCollection 2020 Jan 9.

Authors

Daniel E Jeffries¹, Corina M Borza², 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.

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.

Abstract

Grants and funding