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- Title
Small Molecule c-KIT Inhibitors for the Treatment of Gastrointestinal Stromal Tumors: A Review on Synthesis, Design Strategies, and Structure–Activity Relationship (SAR).
- Authors
Godesi, Sreenivasulu; Lee, Joohan; Nada, Hossam; Quan, Guofeng; Elkamhawy, Ahmed; Choi, Yongseok; Lee, Kyeong
- 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.
- Subjects
C-kit protein; GASTROINTESTINAL stromal tumors; STRUCTURE-activity relationships; SMALL molecules; PHARMACEUTICAL chemistry
- Publication
International Journal of Molecular Sciences, 2023, Vol 24, Issue 11, p9450
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms24119450