Journal Article

Inhibitors of Discoidin Domain Receptor (DDR) Kinases for Cancer and Inflammation

Flanagan, Jack U., Denny, William A.

2021

Overview

The discoidin domain receptor tyrosine kinases DDR1 and DDR2 are distinguished from other kinase enzymes by their extracellular domains, which interact with collagen rather than with peptidic growth factors, before initiating signaling via tyrosine phosphorylation. They share significant sequence and structural homology with both the c-Kit and Bcr-Abl kinases, and so many inhibitors of those kinases are also effective. Nevertheless, there has been an extensive research effort to develop potent and specific DDR inhibitors. A key interaction for many of these compounds is H-bonding to Met-704 in a hydrophobic pocket of the DDR enzyme. The most widespread use of DDR inhibitors has been for cancer therapy, but they have also shown effectiveness in animal models of inflammatory conditions such as Alzheimer’s and Parkinson’s diseases, and in chronic renal failure and glomerulonephritis.

• Publisher: MDPI AG,MDPI
• Subject: Animal models / Animals / BCR-ABL protein / Binding sites / c-Kit protein / Cancer / Collagen / DDR kinase inhibitors / Discoidin Domain Receptor 1 - antagonists & inhibitors / Discoidin Domain Receptor 1 - chemistry / Discoidin Domain Receptor 1 - metabolism / Discoidin Domain Receptor 2 - chemistry / Discoidin Domain Receptor 2 - metabolism / Discoidin Domain Receptors - chemistry / Discoidin Domain Receptors - metabolism / Enzymes / Fusion protein / Glomerulonephritis / Growth factors / Homology / Humans / Hydrogen bonds / Hydrophobicity / Inflammation / Inflammation - drug therapy / Inflammation - metabolism / Kidney diseases / Kinases / Melanoma / Neoplasms - drug therapy / Neoplasms - enzymology / Neoplasms - metabolism / Phosphorylation / Protein Kinase Inhibitors - chemistry / Protein Kinase Inhibitors - pharmacology / Protein Kinase Inhibitors - therapeutic use / Proteins / Renal failure / selectivity / small molecules / Tyrosine