TARGETING ONCOGENIC KINASE SIGNALING WITH SMALL MOLECULE KINASE INHIBITOR IMATINIB

Protein tyrosine kinases (PTKs) are key players in cellular signal transduction events and have essential roles in cell growth, survival, differentiation and migration. Perturbations in protein tyrosine kinase activity have been implicated in a number of abnormalities, particularly cancer. Selective small molecule inhibitors are potential therapeutic agents targeting protein kinases involved in cancer and other diseases. The most dramatic clinical responses have been observed in cancer types that are strictly dependent on oncogenic kinases. In this case, targeting these kinases seems to be sufficient to provoke apoptotic response, thus limiting the process of tumorigenesis. Among tyrosine kinase inhibitors, imatinib mesylate (Gleevec®; Novartis) has demonstrated magnificent clinical efficacy in more than one type of cancer and received FDA approval for treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST). Imatinib has set a paradigm for the treatment and management of CML as BCR-ABL kinase inhibitor. It binds kinase domain of PTK as an ATP-competitive inhibitor thus preventing the interaction with effector proteins and subsequent signaling pathway. Imatinib has excellent pharmacokinetic profile and therapy is generally well tolerated with mild to moderate toxicity which is manageable on reduction or discontinuation of dosage. Despite its tremendous clinical outcome, patients with advanced disease harbor resistance which is perhaps multifactorial. Currently there is requisite of making strategies to overcome resistance mechanisms and adverse effects in order to provide maximum benefit to the patients.