A holistic view on c-Kit in cancer: Structure, signaling, pathophysiology and its inhibitors

Receptor tyrosine kinases play an important role in many cellular processes, and their dysregulation leads to diseases, most importantly cancer. One such receptor tyrosine kinase is c-Kit, a type-III receptor tyrosine kinase, which is involved in various intracellular signaling pathways. The role of different mutant isoforms of c-Kit has been established in several types of cancers. Accordingly, promising c-Kit inhibition results have been reported for the treatment of different cancers (e.g., gastrointestinal stromal tumors, melanoma, acute myeloid leukemia, and other tumors). Therefore, lots of effort has been put to target c-Kit for the treatment of cancer. Here, we provide a comprehensive compilation to provide an insight into c-Kit inhibitor discovery. This compilation provides key information regarding the structure, signaling pathways related to c-Kit, and, more importantly, pharmacophores, binding modes, and SAR analysis for almost all small-molecule heterocycles reported for their c-Kit inhibitory activity. This work could be used as a guide in understanding the basic requirements for targeting c-Kit, and how the selectivity and efficacy of the molecules have been achieved till today. [Display omitted] •c-Kit, a type III receptor tyrosine kinases, is known to play a critical role in occurrence and proliferation of cancer.•ATP-binding site in c-Kit contains bound Mg2+ ion, which lies in the cleft between the N- and C-lobes.•It is involved in the activation of different signaling pathways including MAPK, PI3K, etc.•c-Kit inhibitors possess pharmacophoric features including a head, hinge binding feature, a linker and a tail.