Abstract

COMPARATIVE DOCKING AND MUTATIONAL STUDIES CKIT AND PDGFR A INHIBITORS IN GASTROINTESTINAL STROMAL TUMORS

Aishwarya Mandava*, Pranusha Reddy Mallepalli, Dharani Matha, Pushpa Ragini

Abstract

Background: Gastrointestinal stromal tumor (GIST) is a type of sarcoma found in the digestive system, most often in the wall of the stomach. Some GISTs are not cancerous (they are benign.) But they can become cancerous if not treated. Mutually exclusive KIT and PDGFRA mutations are central events in GIST pathogenesis. Mutations in KIT can be found in about 80% of GISTs. However, about 10% of GISTs have a normal KIT gene (wildtype) but show mutations in the gene for PDGFRA. Mutations in the KIT gene that are relevant for GISTs are found in exons 9, 11, 13 and 17.Mutations in the PDGFR gene that are relevant for GISTs are found in exons 12,14 and 18. Response of GIST patients to tyrosine kinase inhibitors varies by the specific mutation displayed by their tumors. Targeting receptor tyrosine kinases by tyrosine kinase inhibitors (TKIs) thereby blocking kinase domain prevents the phosphorylation of the receptor at TK domain and interferes with cell proliferation, differentiation, migration, and survival and induces cell apoptosis. Method: Thirty six Tyrosine kinase inhibitors were targeted against the c-KIT protein. The first fifteen TKIs that had good binding affinity were docked with the mutatnts developed (D816V, K642E,V654A) and the results of these TKIs were compared. Twenty Tyrosine kinase inhibitors were targeted against kinase domain of PDGFRA protein. The first seven TKIs that had good binding affinity were docked with the mutants developed(D842V, D842Y) and the TKIs were compared based on the results.

Keywords: Gastrointestinal stromal tumor (GIST),KIT,PDGFRA,Mutation.