Small Molecule Discoidin Domain Receptor Kinase Inhibitors and Potential Medical Applications

Abstract

Discoidin domain receptors (DDRs) are members of the transmembrane receptor tyrosine kinase (RTK) superfamily which are distinguished from others by the presence of a discoidin motif in the extracellular domain and their utilization of collagens as internal ligands. Two types of DDRs, DDR1 and DDR2, have been identified with distinct expression profiles and ligand specificities. These DDRs play important roles in the regulation of fundamental cellular process, such as proliferation, survival, differentiation, adhesion, and matrix remodeling. They have also been closely linked to a number of human diseases, including various fibrotic disorders, atherosclerosis, and cancer. As a consequence, DDRs have been considered as novel potential molecular targets for drug discovery and increasing efforts are being devoted to the identification of new small molecule inhibitors targeting the receptors. In this review, we offer a contemporary overview on the discovery of DDRs inhibitors and their potential medical application for the treatment of cancer and inflammation related disorders.

Inhibition of Discoidin Domain Receptor 1 Reduces Collagen-mediated Tumorigenicity in Pancreatic Ductal Adenocarcinoma

“…We observed reduced collagen deposition in tumors from mice treated with 7rh, thus the inhibition of DDR1 might improve response to chemotherapy in a cell autonomous manner and also improve drug delivery without disrupting the function of cancer-associated fibroblasts. DDR1 inhibition has also been shown to reduce tumorigenicity in multiple tumor models (23,25,51,52). For example, silencing DDR1 by siRNA has been shown to reduce metastatic activity in lung cancer models (27,51) and enhance chemosensitivity to genotoxic drugs in breast cancer cells (49).…”

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

“…Approaches to block DDR1-mediated effects include: reduction of DDR1 expression by using antisense nucleotide [8,33], inhibition of DDR1 binding to collagen with recombinant engineered bacterial collagen [34], inhibition of DDR1 oligomerization with selective monoclonal antibodies [35], and inhibition of DDR1 tyrosine kinase activity (see also [12]). As DDR1 ATP-competitive inhibitors with good selectivity have been developed [26,36–39] targeting the kinase activity of DDR1 has become an appealing strategy. 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).…”

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.…”