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

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.

Automated summary

The proto-oncogenic protein c-KIT is crucial in regulating cellular transformation and differentiation, and dysregulation of c-KIT can lead to various human cancers, especially GISTs. Current approved drugs have limitations, highlighting the need for selective c-KIT inhibitors. Recent research efforts in medicinal chemistry discuss the development of potent c-KIT inhibitors with high selectivity for GISTs.