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Review
. 2021 Nov 10;11(11):1671.
doi: 10.3390/biom11111671.

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

William A Denny  1 , Jack U Flanagan  1   2
Affiliations
Review

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

William A Denny et al. Biomolecules. .

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.

Keywords: DDR kinase inhibitors; selectivity; small molecules.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Generic structures of DDR1 and DDR2. DS, N-terminal discoidin domain; DS-like, discoidin-like domain [3]; EJXM, extracellular juxtamembrane domain; TM, trans-membrane domain; IJXM, intracellular juxtamembrane domain; KD, kinase domain. After [10].
Figure 2
Figure 2
(A) DDR inhibitors can be divided into three regions based on the location in the ATP binding site. (B) ATP binding site location between the N- and C-terminal lobes of the kinase domain (cyan surface). (C–E) Binding modes for compounds 8–10 in the DDR1 ATP binding site (PBD codes 6GWR, 5FDP and 4CKR, respectively). The colored boxes represent the head (black), linker (blue) and tail (red) units. The hydrogen bond with Met-704 is indicated with the dashed bond. Hydrogen bonds with the side chain of Glu-672 and with the backbone amide of Asp-784 are also shown. (Images created with PyMol).
Figure 3
Figure 3
(A) Selective DDR inhibitors. (B–D) Hydrophobic back pocket and selectivity pockets targeted by some selective compounds 8–10 (PBD entries 6GRW, 5FDP and 4CKR, respectively) (image created with PyMol).
Figure 3
Figure 3
(A) Selective DDR inhibitors. (B–D) Hydrophobic back pocket and selectivity pockets targeted by some selective compounds 8–10 (PBD entries 6GRW, 5FDP and 4CKR, respectively) (image created with PyMol).
Figure 4
Figure 4
Selective DDR1 inhibitors.
Figure 5
Figure 5
Allosteric DDR inhibitors.
Figure 6
Figure 6
DDR inhibitors in the patent literature.
Figure 7
Figure 7
DDR inhibitors in cancer treatment.
Figure 8
Figure 8
DDR inhibitors for inflammatory conditions.
Figure 9
Figure 9
DDR inhibitors in brain disease.
See this image and copyright information in PMC

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References

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