Small Molecule Tyrosine Kinase Inhibitors: The New Dawn for Cancer Therapy

Malleshappa      N. Noolvi; Harun      M. Patel

Abstract

Tyrosine kinases are important mediators of the signaling cascade, determining key roles in diverse biological processes like growth, differentiation, metabolism and apoptosis in response to external and internal stimuli. Recent advances have implicated the role of tyrosine kinases in the pathophysiology of cancer. Though their activity is tightly regulated in normal cells, they may acquire transforming functions due to mutation(s), overexpression and autocrine paracrine stimulation, leading to malignancy. Constitutive oncogenic activation in cancer cells can be blocked by selective small molecule tyrosine kinase inhibitors and thus considered as a promising approach for innovative therapeutics. The remarkable success of BCR-ABL tyrosine kinase inhibitor imatinib (STI571) in the treatment of chronic myeloid leukaemia has particularly stimulated intense research in this field. At least 30 inhibitors are in various stages of clinical development in cancer, and about 120 clinical trials are ongoing worldwide. In this review, we focus on the role of tyrosine kinases in cancer and the development of specific small molecule inhibitors for therapy. We also provide a critical analysis of the current data on tyrosine kinase inhibitors and highlight areas for future research. Issues with regards to the design of clinical trials with such agents are also discussed. Herein, we also discussed the different synthetic pathway for the synthesis of small molecule inhibitors along with their pharmacokinetic, different mechanisms of resistance and side effects.

Keywords: Tyrosine kinase, Cancer, Small Molecule Inhibitors, Pharmacokinetic, Resistance, BCR-ABL, STI571, malignancies, Bcr/Abl fusion, Tel/PDGFR, ATP-binding domain, tinibs, EGF