Inhibitors of Cellular Signaling Targets: Designs and Limitations

Kinases carry out the reversible phosphorylation of proteins and lipids, and are responsible for direct or indirect control of almost every signaling pathway in cells, leading to responses such as proliferation, differentiation, metabolism, transport, and gene expression. It is estimated that the human genome may contain about 1000 kinases (1 ). To date, approx 500 protein kinases have been identified, of which about 400 are serine/threonine kinases and approx 100 are tyrosine kinases. Because of their central role in cellular signaling, as well as their primary role in disease progression, protein kinases are attractive therapeutic targets (2 ,3 ). Seven molecules targeting protein kinases, imatinib mesylate (Gleevec) and trastuzumab (Herceptin), an inhibitor of BCR-abl and an antibody against ERB-2, respectively, are currently marketed as anti-oncolytics (4 –7 ). In addition, six molecules that block kinase activity are currently being investigated in Phase III clinical trials, whereas as many as 30 candidates targeting kinases are in early clinical development (Phase I or Phase II) (8 ,9 ).