Novel Protein Kinase Inhibitors: SMART Drug Design Technology

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In retrospect, the emergence of protein kinase drug discovery dates to the identification of the first oncogenic protein kinase, Src, about 25 years ago. This work has led to worldwide research efforts to investigate the genomic and proteomic relationships of protein kinases in disease, cellular mechanisms involving protein kinases in signal transduction, structural biology and modes of both activation and inhibition of protein kinases, and drug discovery focused on novel protein kinase inhibitors (1–20). It is now known that protein kinases constitute a superfamily of therapeutic targets that include >500 members relative to recent sequencing of the human genome (21–23). Key classes of protein kinases (Table 1) include receptor tyrosine kinases (e.g., epidermal growth factor receptor [EGFR], platelet-derived growth factor receptor [PDGFR], and vascular endothelial growth factor receptor [VEGFR]), nonreceptor tyrosine kinases (e.g., Src and Abl), receptor serine/threonine kinases (e.g., transforming growth factor receptor [TGFR]), and nonreceptor serine/threonine and dual specificity kinases (e.g., cyclin-dependent kinase [CDK], m-Tor, and MEK). The tyrosine kinases comprise about 20% of known or predicted protein kinases. As highlighted in Figures 1 and 2, key milestones and advances in protein kinase inhibitor drug discovery include focused studies on protein kinase C (PKC), CDK, MEK, p38 mitogen-activated protein kinase (MAPK), Abl kinase, Src kinase, insulin receptor kinase (IRK), and EGFR kinase. Such work has embraced an increased understanding of the roles of protein kinases in signal transduction pathways, including aberrant cellular mechanisms underlying cancer (e.g., PKC, CDK, Abl kinase, Src kinase, and several growth factor receptor kinases). Structural studies have contributed significantly to recent drug discovery campaigns (e.g., nonreceptor kinases, such as Src, Lck, and Abl kinase, and several growth factor receptor kinases). Although the major mode of inhibition of protein kinases has been focused on the ATP binding site, there have been recent achievements made to exploit both allosteric and substrate binding site interactions to advance novel molecules (vide infra). Importantly, very recent Food and Drug Administration (FDA) approvals of both Gleevec (STI-571; Novartis AG International, Basel, Switzerland) (24–26) and Iressa® (ZD1839; AstraZeneca, Wilmington, De, USA) (27–29) exemplify success in drug development of tyrosine kinase inhibitors with particular therapeutic indications for certain cancers.