Multiple approaches have been developed to profile the kinase selectivity of small molecules. Therefore, an accurate method for comprehensive off-target profiling of kinase drug candidates is essential for kinase inhibitor design and assessment of drug safety and efficacy. However, unintentional off-target drug binding have already proven to contribute to severe side-effects and dose-limiting toxicities from numerous clinical and preclinical studies ( Tabernero, 2007). Similarly, multi-targeted tyrosine kinase inhibitors like sunitinib, a potent inhibitor of VEGFR1, VEGFR2, FLT3, KIT, PDGFRα and PDGFRβ could counter drug resistance by preventing ‘signal rewiring’ in cancer treatment. For example, although imatinib was originally developed as a selective ABL inhibitor, the discovery of its unexpected activity against KIT has led to the approval of imatinib for the treatment of GIST ( Demetri et al., 2002). Since the majority of kinase inhibitors bind within the ATP binding region, unintended inhibitor off-target binding can occur due to high structural homology across kinase ATP binding pockets, resulting in either favorable interactions or adverse events ( Hanks et al., 1988). Several well-known druggable kinases include stem-cell factor receptor (KIT) for gastrointestinal tract stromal tumors (GIST), proto-oncogene tyrosine-kinase receptor (RET) for medullary thyroid carcinoma (MTC) and fetal liver tyrosine-protein kinase receptor 3 (FLT3) for acute lymphocytic leukemia (ALL) ( Akeno-Stuart et al., 2007 Druker et al., 2001 Helguera et al., 2006 Rosnet et al., 1991 Verweij et al., 2004). Following the discovery of the Abelson murine leukemia viral oncogene homolog (ABL)-targeting agent imatinib (Gleevec) as a highly successful treatment for chronic myeloid leukemia (CML), numerous other kinase targets have been actively pursued for cancer therapy. Consequently, designing selective kinase inhibitors that target specific cellular pathways, known as ‘targeted therapy,’ has been a major focus area in the pharmaceutical industry. Many kinases have been implicated in a wide variety of diseases including cancers, inflammatory diseases and metabolic syndrome and are potential therapeutic targets ( Momcilovic et al., 2017 Patterson et al., 2014). Based on cellular localization and the residue(s) of phosphorylation, human protein kinases can be classified as receptor or non-receptor kinases and tyrosine, serine/threonine, or dual kinases, respectively. The human kinome consists of ∼500 protein kinases that regulate diverse cellular process including metabolism, apoptosis, immune response, cell growth and proliferation ( Braconi Quintaje and Orchard, 2008 Manning et al., 2002).
0 kommentar(er)
