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Review
. 2023 May 29;24(11):9450.
doi: 10.3390/ijms24119450.

Small Molecule c-KIT Inhibitors for the Treatment of Gastrointestinal Stromal Tumors: A Review on Synthesis, Design Strategies, and Structure-Activity Relationship (SAR)

Sreenivasulu Godesi  1 , Joohan Lee  1 , Hossam Nada  1 , Guofeng Quan  1 , Ahmed Elkamhawy  1   2 , Yongseok Choi  3 , Kyeong Lee  1
Affiliations
Review

Small Molecule c-KIT Inhibitors for the Treatment of Gastrointestinal Stromal Tumors: A Review on Synthesis, Design Strategies, and Structure-Activity Relationship (SAR)

Sreenivasulu Godesi et al. Int J Mol Sci. .

Abstract

The proto-oncogenic protein, c-KIT, plays a crucial role in regulating cellular transformation and differentiation processes, such as proliferation, survival, adhesion, and chemotaxis. The overexpression of, and mutations, in c-KIT can lead to its dysregulation and promote various human cancers, particularly gastrointestinal stromal tumors (GISTs); approximately 80-85% of cases are associated with oncogenic mutations in the KIT gene. Inhibition of c-KIT has emerged as a promising therapeutic target for GISTs. However, the currently approved drugs are associated with resistance and significant side effects, highlighting the urgent need to develop highly selective c-KIT inhibitors that are not affected by these mutations for GISTs. Herein, the recent research efforts in medicinal chemistry aimed at developing potent small-molecule c-KIT inhibitors with high kinase selectivity for GISTs are discussed from a structure-activity relationship perspective. Moreover, the synthetic pathways, pharmacokinetic properties, and binding patterns of the inhibitors are also discussed to facilitate future development of more potent and pharmacokinetically stable small-molecule c-KIT inhibitors.

Keywords: GISTs; SAR; SCFR; c-KIT; c-KIT inhibitors; stem cell growth factor.

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Conflict of interest statement

The authors have declared no conflict of interest.

Figures

Figure 1
Figure 1
Structure of the KIT receptor. The main mutation sites and phosphorylation sites of KIT in GISTs. Reprinted and modified from Ref. [15].
Figure 2
Figure 2
Chemical structures of KIT inhibitors approved for the treatment of GISTs.
Figure 3
Figure 3
SAR summary and pharmacophore description of substituted N-(4-methyl-3-(piperidin-4-yloxy)phenyl) analogs.
Figure 4
Figure 4
(A) docking of 6e into c-KIT kinase (PDB ID: 1T46) (B) docking of 6e into ABL kinase (PDB ID: 2HYY) (C) Superimposition of docking model of 6e with ABL kinase (PDB ID: 2HYY) (in white) and 1-ABL kinase X-ray crystal structure (in purple). (D) Superimposition of 6e with c-KIT kinase (PDB ID: 1T46) (in white) and docked model of 6e with ABL kinase (PDB ID: 2HYY) (in purple). Reprinted with permission from Ref. [40].
Figure 5
Figure 5
Discovery, SAR summary, and pharmacophore description of quinoline-based urea derivatives as c-KIT wt and c-KIT T670I inhibitors.
Figure 6
Figure 6
(A) Molecular modeling of compound 22aa with c-KIT wt (PDB code 1T46); (B) Molecular modeling of compound 22aa with the c-KIT T670I homology model (generated based on PDB code 1T46). Reprinted with permission from Ref. [41].
Figure 7
Figure 7
Discovery, SAR summary, and pharmacophore description of compound 35h from 22aa to improve the pharmacokinetic profile.
Figure 8
Figure 8
Molecular docking analysis of 35h (A) 35h with the c-KIT wt (PDB code: 6GQK); (B) 35h with the c-KIT V654A homology model (PDB code: 6GQK); Reprinted with permission from Ref. [42].
Figure 9
Figure 9
Design, optimization strategy, SAR summary, and pharmacophore description for the discovery of compound 57d.
Figure 10
Figure 10
(A) Binding mode of 57d with c-KIT wt (PDB code: 1T46). (B) Binding mode of 57d with c-KIT T670I (PDB code: 1T46). Reprinted with permission from Ref. [43].
Figure 11
Figure 11
Design strategy, SAR summary, and pharmacophore description of ponatinib structure-modified derivatives.
Figure 12
Figure 12
(A) Docking of 71g in complex with wild-type KIT. (B) Close-up view of the back pocket. Reprinted with permission from Ref. [44].
Figure 13
Figure 13
Schematic design, SAR summary, and pharmacophore description for the discovery of compound 75.
Figure 14
Figure 14
Cocrystal structure of 75 bound to c-KIT (PDB code: 6GQM). Reprinted with permission from Ref. [45].
Figure 15
Figure 15
SAR summary and pharmacophore description of 81a.
Figure 16
Figure 16
Chemical structure of 81A and in complex with the unactivated c-KIT kinase domain (PDB 6ITT). Reprinted with permission from Ref. [48].
Figure 17
Figure 17
Rational design, SAR summary, and pharmacophore description of compound 105a.
Figure 18
Figure 18
Interactions of 105a in complex with c-KIT and the chemical structure of 105a. Reprinted with permission from Ref. [49].
Figure 19
Figure 19
Design strategy, SAR summary, and pharmacophore description of compound 130d.
Figure 20
Figure 20
Design strategy, SAR summary, and pharmacophore description of compound 135j.
Figure 21
Figure 21
X-ray structure of 135j (2.1 A resolution, PDB-ID: 7ZW8) in complex with the kinase domain of c-KIT. Reprinted with permission from Ref. [51].
Figure 22
Figure 22
SAR summary and chemical structures of compounds 142r and 143c.
Figure 23
Figure 23
(A,B) Docking model of compound of 142r and 143c on c-KIT (PDB code: 1T46). Reprinted from Ref. [52].
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