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.
(Copyright © 2021 Elsevier B.V. All rights reserved.)