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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

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 compounds1–11.
Figure 3
Figure 3
Chemical structure of compound12.
Figure 4
Figure 4
(A) Chemical structures of compounds13 and14; (B) X-ray co-crystal structure of compound13 with DDR1 kinase. Reprinted with permission from Ref. [133]; (C) Compound14 docking model into the DDR1 G707A mutation. Reprinted with permission from Ref. [132].
Figure 4
Figure 4
(A) Chemical structures of compounds13 and14; (B) X-ray co-crystal structure of compound13 with DDR1 kinase. Reprinted with permission from Ref. [133]; (C) Compound14 docking model into the DDR1 G707A mutation. Reprinted with permission from Ref. [132].
Figure 5
Figure 5
Restricted conformation strategy and chemical structures of compounds15 and16.
Figure 6
Figure 6
Chemical structures of DDR1inhibitors17,18 (7RH),19, and20.
Figure 7
Figure 7
Drug design approaches and chemical structures of compounds21–23.
Figure 8
Figure 8
Docking models of compounds21 (A) and23 (B) into DDR1 binding pocket. Reprinted from Ref. [139].
Figure 9
Figure 9
Chemical structures of compound24–28 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 compound34. 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 compounds33 and34. 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 compounds36–38 derived from sorafenib (9).
Figure 15
Figure 15
Docking models of compounds36 (orange) and38 (green) into DFG-out conformation of DDR1. Reprinted with permission from Ref. [146].
Figure 16
Figure 16
(A) Chemical structure of compound39; (B) Both compounds39 (orange) and dasatinib (1) (yellow) overlayed in the active site residue of DDR1 kinase (PDB ID: 5BVW); (C) docking of compound39 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 compound40 and chemical structure of compound41.
Figure 18
Figure 18
Chemical structures of compounds42–44 and docking model of compound42 into DDR2 active site. Reprinted with permission from Ref. [150].
Figure 19
Figure 19
Structural-based design and chemical structures of compounds45 and46. 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 compound20 to afford compound51. Reprinted from Ref. [154].
Figure 22
Figure 22
Structural-based design of compound52–54. Reprinted with permission from Ref. [155].
Figure 23
Figure 23
Chemical structure of compound55.
Figure 24
Figure 24
Chemical structure of compound56 and its docking model to DDR1 active site. Reprinted with permission from Ref. [157].
Figure 25
Figure 25
Chemical structure of compounds57–59.
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References

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