Molecular Recognition of Protein Kinase Binding Pockets for Design of Potent and Selective Kinase Inhibitors

• Published in: Journal of medicinal chemistry 2007-02, Vol.50 (3), p.409-424
• Main Author: Liao, Jeffrey Jie-Lou
• Format: Article
• Language: English
• Subjects: Analytical, structural and metabolic biochemistry; Binding Sites; Biological and medical sciences; Catalytic Domain; Drug Design; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Humans; Medical sciences; Miscellaneous; Models, Molecular; Pharmacology. Drug treatments; Protein Binding; Protein Kinase Inhibitors - chemistry; Protein Kinases - chemistry; Transferases
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0608107

Protein kinases constitute one of the largest protein families in humans. The kinase enzymes in this family catalyze phosphorylation of serine, threonine, or tyrosine residues, regulate the majority of signal transduction pathways in cells, and thus play an important role in cell growth, metabolism, differentiation, and apoptosis. Deregulation of protein kinases is implicated in a number of diseases including cancer, diabetes, and inflammation. Targeted inhibition of protein kinases has thereby become an attractive therapeutic strategy in the treatment of relevant diseases. All kinase enzymes share a catalytic domain that contains a cleft where adenosine triphosphate (ATP super(a)) binds. This catalytic cleft is a major focus of small-molecule drug design for protein kinases. Breakthrough advances over the past decade have so far resulted in several small-molecule kinase inhibitors approved for clinical use by U.S. Food and Drug Administration (FDA). These kinase drugs include imatinib mesylate (STI571,1) (Novartis, 2001), gefitinib (ZD1839, 2) (AstraZeneca, 2003), erlotinib (OSI 774, 3) (Genentech and OSIP, 2004), sorafenib tosylate (Bay 43-9006, 4) (Bayer and Onyx, 2005), sunitinib malate (SU11248, 5) (Pfizer, 2006), and dasatinib (BMS-354825, 6) (Bristol-Myers Squibb, 2006). Their structural formulas are given in Figure 1. The successes of these drugs in specific patient populations have stimulated enthusiasm for investment in the field. Currently, it is estimated that approximately one-third of drug discovery programs target protein kinases. Despite the substantial achievements in protein kinase drug discovery, design of potent inhibitors with high degrees of selectivity during lead optimization remains a major challenge. Many kinase inhibitors have failed in preclinical or clinical development because of the lack of such selectivity that induces intolerable side effects, mostly because the catalytic cleft is highly conserved in sequence and conformation. Systematic analysis of the crystal structures of protein kinases can offer insight into the design of highly selective kinase inhibitors to overcome these effects.