Novel KIT-targeted agents to treat GIST should therefore comprise an increased specificity for KIT while at the same time displaying a reduced ability to inhibit ABL1.
Imatinib, first designed to competitively inhibit the ATP-binding pocket of the BCR-ABL tyrosin kinase exhibits inhibition also in the KIT and PDGFRα tyrosine kinases, which revolutionized the therapy of gastrointestinal stromal tumors, a disease without any systemic treatment options prior to imatinib.
Chronic myeloid leukemia, gastrointestinal stromal tumors (GISTs), and idiopathic hypereosinophilic syndrome are associated with pathological deregulation of the tyrosine kinases BCR-ABL, KIT, and PDGFRA, respectively.
Imatinib, a tyrosine kinase inhibitor of BCR-ABL, KIT, and platelet-derived growth factor receptor, is used in patients with chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GIST).
Imatinib is a selective tyrosine kinase inhibitor of ABL, platelet-derived growth factor receptor (PDGFR), and KIT and represents a new paradigm of targeted therapy against GISTs.
The tyrosine kinase inhibitor STI571, active against the BCR-ABL fusion protein in chronic myeloid leukemia, was recently shown to be highly effective in GISTs.