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

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.

What Have We Learned from Molecularly Informed Clinical Trials on Thymomas and Thymic Carcinomas—Current Status and Future Directions?

“…c-KIT is a proto-oncogene that plays a critical role in cell proliferation, differentiation, and survival encoding for the receptor tyrosine kinase protein KIT (CD117) or mast/stem cell growth factor receptor (SCFR) [59]. These receptors are expressed on numerous cell types, including hematopoietic stem cells.…”

“…These receptors are expressed on numerous cell types, including hematopoietic stem cells. In particular, the capacity to self-renew in cancer cells has been associated with mutations in c-KIT, resulting in constitutive activation [59]. Activating mutations were seen in a variety of cancers, including gastrointestinal stromal tumors (GIST), testicular seminomas, and extracutaneous melanomas [60][61][62].…”