Abstract
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.
Highlights
The discoidin domain kinase inhibitors DDR1 and DDR2 conform to the broad structural organisation of receptor tyrosine kinase enzymes, but are distinguished from the other 58-odd human receptor tyrosine kinases in that their extracellular domains interact with collagen rather than with peptide-like growth factors [1]
Many papers have shown that the over-expression/mutation of DDR1 is associated with multiple cancers, including major types such as lung, breast, brain, liver, pancreas and prostate [5], and that this over-expression/mutation promotes significant disease progression on a large number of non-cancer disease states caused by various inflammatory conditions, including fibrosis [6], atherosclerosis [7] and liver/kidney dysfunction [8,9]
This was initially sparked by the overlapping activity of previously showed that DDR1-deficient mice were protected from induced glomerulonephritis, and developed c-Kit and Bcr-Abl inhibitors, resulting from the relatively high sequence and structural homology of their kinase domains with those of the DDRs
Summary
The discoidin domain kinase inhibitors DDR1 and DDR2 conform to the broad structural organisation of receptor tyrosine kinase enzymes (cellular domain, membrane domain, extracellular domain), but are distinguished from the other 58-odd human receptor tyrosine kinases in that their extracellular domains interact with collagen rather than with peptide-like growth factors [1]. Unlike most growth-factor-receptor-linked tyrosine kinases, which are activated by dimerization upon ligand binding and autophosphorylation, DDRs have to dimerize to allow binding (to collagen) and initiate tyrosine phosphorylation [3,4]. EJXM, extracellular juxtamembrane domain; TM, trans-membrane domain; IJXM, intracellular juxtamembrane domain; KD, coidin-like domain kinase domain. After [10].[3]; EJXM, extracellular juxtamembrane domain; TM, trans-membrane doma. IJXM, intracellular juxtamembrane domain; KD, kinase domain. With the most important use of DDR inhibitors has been in cancer therapy, and
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