Ripretinib (DCC-2618) was designed to inhibit the full spectrum of mutant KIT and PDGFRA kinases found in cancers and myeloproliferative neoplasms, particularly in gastrointestinal stromal tumors (GISTs), in which the heterogeneity of drug-resistant KIT mutations is a major challenge.
Oncogenic mutations of FLT3 and KIT receptors are associated with poor survival in patients with acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPNs), and currently available drugs are largely ineffective.
Although mutations in the receptor tyrosine kinase KIT have been identified in patients with myeloproliferative neoplasm, the functional causality is unknown because of a lack of animal models.
The KITD816V mutation is one of the minor criteria for a diagnosis of SM according to the 2008 World Health Organization classification of myeloproliferative neoplasms.
Overexpression of KIT, a tyrosine kinase receptor protein encoded by the proto-oncogene c-kit, is observed in human neoplasms such as gastrointestinal stromal tumors (GISTs), myeloproliferative disorders, melanoma and seminoma.
Mutations causing constitutive activation of KIT have been shown to be causative in some forms of mastocytosis, and several types of mutations have been associated with myeloproliferative disorders (MPDs), acute myelogenous leukemia (AML), sinonasal lymphomas, and gastrointestinal stromal tumors (GIST).