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Review
. 2021 Jun 18;22(12):6535.
doi: 10.3390/ijms22126535.

The Journey of DDR1 and DDR2 Kinase Inhibitors as Rising Stars in the Fight Against Cancer

Ahmed Elkamhawy  1   2 , Qili Lu  1 , Hossam Nada  1 , Jiyu Woo  1 , Guofeng Quan  1 , Kyeong Lee  1
Affiliations
Review

The Journey of DDR1 and DDR2 Kinase Inhibitors as Rising Stars in the Fight Against Cancer

Ahmed Elkamhawy et al. Int J Mol Sci. .

Abstract

Discoidin domain receptor (DDR) is a collagen-activated receptor tyrosine kinase that plays critical roles in regulating essential cellular processes such as morphogenesis, differentiation, proliferation, adhesion, migration, invasion, and matrix remodeling. As a result, DDR dysregulation has been attributed to a variety of human cancer disorders, for instance, non-small-cell lung carcinoma (NSCLC), ovarian cancer, glioblastoma, and breast cancer, in addition to some inflammatory and neurodegenerative disorders. Since the target identification in the early 1990s to date, a lot of efforts have been devoted to the development of DDR inhibitors. From a medicinal chemistry perspective, we attempted to reveal the progress in the development of the most promising DDR1 and DDR2 small molecule inhibitors covering their design approaches, structure-activity relationship (SAR), biological activity, and selectivity.

Keywords: DDR1 and DDR2; cancer; discoidin domain receptor (DDR); kinase inhibitors; structure-activity relationship (SAR).

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structures and subtypes of DDR1 and DDR2. Reprinted from with permission Ref. [13].
Figure 2
Figure 2
Chemical structures of compounds 1–11.
Figure 3
Figure 3
Chemical structure of compound 12.
Figure 4
Figure 4
(A) Chemical structures of compounds 13 and 14; (B) X-ray co-crystal structure of compound 13 with DDR1 kinase. Reprinted with permission from Ref. [133]; (C) Compound 14 docking model into the DDR1 G707A mutation. Reprinted with permission from Ref. [132].
Figure 4
Figure 4
(A) Chemical structures of compounds 13 and 14; (B) X-ray co-crystal structure of compound 13 with DDR1 kinase. Reprinted with permission from Ref. [133]; (C) Compound 14 docking model into the DDR1 G707A mutation. Reprinted with permission from Ref. [132].
Figure 5
Figure 5
Restricted conformation strategy and chemical structures of compounds 15 and 16.
Figure 6
Figure 6
Chemical structures of DDR1inhibitors 17, 18 (7RH), 19, and 20.
Figure 7
Figure 7
Drug design approaches and chemical structures of compounds 21–23.
Figure 8
Figure 8
Docking models of compounds 21 (A) and 23 (B) into DDR1 binding pocket. Reprinted from Ref. [139].
Figure 9
Figure 9
Chemical structures of compound 24–28 designed based on 7RH (18) as a lead molecule.
Figure 10
Figure 10
Chemical structures of type II and III DFG-out binders for DDR2 (29–32).
Figure 11
Figure 11
Schematic of the design process leading to discovery of compound 34. Reprinted with permission from Ref. [142].
Figure 12
Figure 12
(A) Fragment 1 (33) in DDR1 binding pocket; (B) Cocomplex of dasatinib (1) and fragment 1 (33) (C) Cocomplex of compounds 33 and 34. Reprinted with permission from Ref. [142].
Figure 13
Figure 13
Chemical structure of compound KST9046 (35).
Figure 14
Figure 14
Structure-based design strategy of compounds 36–38 derived from sorafenib (9).
Figure 15
Figure 15
Docking models of compounds 36 (orange) and 38 (green) into DFG-out conformation of DDR1. Reprinted with permission from Ref. [146].
Figure 16
Figure 16
(A) Chemical structure of compound 39; (B) Both compounds 39 (orange) and dasatinib (1) (yellow) overlayed in the active site residue of DDR1 kinase (PDB ID: 5BVW); (C) docking of compound 39 within DDR1 active site (D) Docking of dasatinib (1) within DDR1 active site. Reprinted with permission from Ref. [147].
Figure 17
Figure 17
Structural modifications to compound 40 and chemical structure of compound 41.
Figure 18
Figure 18
Chemical structures of compounds 42–44 and docking model of compound 42 into DDR2 active site. Reprinted with permission from Ref. [150].
Figure 19
Figure 19
Structural-based design and chemical structures of compounds 45 and 46. Reprinted with permission from Ref. [151].
Figure 20
Figure 20
Chemical structures of natural alkaloids discoipyrroles A–D (47–50). Reprinted with permission from Ref. [153].
Figure 21
Figure 21
Structural-based design of compound 20 to afford compound 51. Reprinted from Ref. [154].
Figure 22
Figure 22
Structural-based design of compound 52–54. Reprinted with permission from Ref. [155].
Figure 23
Figure 23
Chemical structure of compound 55.
Figure 24
Figure 24
Chemical structure of compound 56 and its docking model to DDR1 active site. Reprinted with permission from Ref. [157].
Figure 25
Figure 25
Chemical structure of compounds 57–59.
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