Discoidin domain receptor 1 (DDR1) kinase as target for structure-based drug discovery

Drug Discov Today. 2015 Feb;20(2):255-61. doi: 10.1016/j.drudis.2014.09.025.

Sandeepkumar Kothiwale ¹, Corina M Borza ², Edward W Lowe Jr ¹, Ambra Pozzi ³, Jens Meiler ⁴

Affiliations

1 Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
2 Department of Medicine, Division of Nephrology, Vanderbilt University, Nashville, TN 37232, USA.
3 Department of Medicine, Division of Nephrology, Vanderbilt University, Nashville, TN 37232, USA; Department of Medicine, Veterans Affairs Hospital, Nashville, TN 37232, USA.
4 Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA. Electronic address: [email protected].

PMID: 25284748 DOI: 10.1016/j.drudis.2014.09.025

Abstract

Discoidin Domain Receptor (DDR) 1 and 2 are transmembrane receptors that belong to the family of Receptor Tyrosine Kinases (RTK). Upon Collagen binding, DDRs transduce cellular signaling involved in various cell functions, including cell adhesion, proliferation, differentiation, migration, and matrix homeostasis. Altered DDR function resulting from either mutations or overexpression has been implicated in several types of disease, including atherosclerosis, inflammation, Cancer, and tissue fibrosis. Several established inhibitors, such as imatinib, dasatinib, and nilotinib, originally developed as Abelson murine leukemia (Abl) kinase inhibitors, have been found to inhibit DDR kinase activity. As we review here, recent discoveries of novel inhibitors and their co-crystal structure with the DDR1 kinase domain have made structure-based drug discovery for DDR1 amenable.

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