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

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.

Discoidin domain receptor 1 kinase activity is required for regulating collagen IV synthesis

“…The majority of tyrosine kinase inhibitors synthetized are ATP-competitive inhibitors which target either the kinase domains in the active form (type I inhibitors) or in the inactive form (type II inhibitors). While type I inhibitors tend to be promiscuous, because they usually target well-conserved active kinase binding sites, type II inhibitors tend to be more selective because they can interact with not-well-conserved exposed hydrophobic sites within the inactive kinase domain [38]. …”

Extracellular matrix component signaling in cancer

“…Since dysregulated DDR activity is often associated with particularly aggressive forms of cancers that currently lack targeted treatment options, the development of DDR-selective inhibitors may be a promising therapeutic avenue for rational cancer treatment. A sharp increase in research related to the development of DDR kinase inhibitors reflects this thinking [140][141][142]. Inhibitors originally developed to target the activity of BCR-ABL kinase are also potent inhibitors of the DDRs [143,144], but these drugs have a very broad specificity and are active against a number of additional kinases.…”

Contribution of collagen adhesion receptors to tissue fibrosis

“…An alternative approach to dismantle DDR function is to target the tyrosine kinase activity of DDRs (e.g., nilotinib) and thereby block DDR-mediated downstream signaling (Borza and Pozzi 2014). Arising from this notion, several small molecule compounds that inhibit the activity of these tyrosine kinases have been identified (Chen et al 2016;Kothiwale et al 2015;Li et al 2015).…”