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Protein Kinase Inhibitors

Interest in the development of protein kinase inhibitors has grown so enormously in the last decade, both in academic and industrial laboratories, that now the protein kinase family is the second most important drug target (Cohen 2002). This is mainly due to the involvement of the superfamily of protein kinases in many key functions of cell life, including cell cycle regulation, development, proliferation, signal transmission, and apoptosis. Abnormalities in the natural roles of this class of enzyme are often associated with human diseases, especially cancer and tumor pathologies, whose treatment has so far been restricted to cytotoxic and hormonal agents (Goel et al. 2002). Even though the application of kinase inhibitors as drugs is a very challenging task, mostly because of the conservation of structural features within the ATP-binding clefts, now many kinase inhibitors are in clinical trials or even in the market, the majority of them as anti-tumor drugs (Cohen 2002).

The estimate that at least 500 different protein kinases are encoded in the human genome makes really challenging the design of molecules that specifically target a single protein without affecting closely related kinases. The targeting of the ATP-binding site has the obvious drawbacks of the existence of other ATP-utilizing proteins and the high intracellular concentrations of ATP. Although peptide inhibitors directed to the substrate binding site may in principle offer a higher degree of specificity, they have their own set of problems that includes low affinity and potential bioavailability issues.

One of the first kinase inhibitors discovered has been staurosporine, that shows a large activity spectrum and therefore a low selectivity. Most protein kinases are inhibited by staurosporine with IC50 in the low nanomolar range. Interestingly, CK2, as well as a few other kinases, is less affected by this inhibitor, with IC50 in the micromolar range. This trait, together with the quite unique ability of CK2 to utilize both ATP and GTP as phosphate donor, suggests an appreciable difference in the structural properties of the active site that potentially can be exploited in the inhibitors optimization process.

The most common chemical scaffolds used as ATP site-directed kinase inhibitors are derivatives of heterocyclic compounds, such as quinazolines, phenylamino- or pyrido- or pyrrolo- or pyrimido- or pyrazolo-pyrimidines, pyrrolo-pyridines, indolin-2-ones, purines, pyridinyl- or pyrimidinyl-imida-zoles, and phthalazines. Some other building blocks are derived from natural products, such as alkaloids, flavonoids, and the aforementioned stau-rosporine (Garcia-Echeverria et al. 2000).

Recently, an insulin receptor tyrosine kinase bisubstrate inhibitor competitive against both nucleotide and peptide substrates has been designed (Parang et al. 2001). The crystal structure of its complex with the protein tyrosine kinase (PTK) has confirmed the double anchoring scheme of target binding. This bisubstrate inhibitor could be a precursor of a new interesting class of anticancer therapeutic agents, allowing the possibility to take advantage of the small differences in the various kinase binding sites to improve the selectivity of the inhibition (Parang and Cole 2002).

The availability of an increasing number of three-dimensional structures of inhibitor/kinases complexes are helping in clarifying the atomic basis for the different selectivity and potency (Toledo et al. 1999). These crystal structures are often the starting point for the optimization of additional analogs through rational drug design approaches. A representative case is that of CDK2, whose crystal structures in complex with a number of key inhibitors has been used to explain the observed structure-activity relationships within the compound series and to guide the design of more potent inhibitors (Gray et al. 1998; Davis et al. 2001; Hardcastle et al. 2002). Nowadays, the first step in the research of a new promising chemical scaffolds is often the running of a virtual screen of a huge amount of chemical compounds utilizing as a target the three-dimensional structure of the protein kinase in complex with some inhibitor (Stahura et al. 1999). A similar approach has been successful in the case of different tyrosine kinases such as epidermal growth factor receptor (EGFR)/ErbB2 kinases, Flt-1 kinase, and Abl kinase (Traxler et al. 2001).

Probably the most exciting result in the field of kinase inhibitors concerns chronic myelogenous leukemia (CML), due to a translocation involving chromosome 8 and 22 that generates the BCR-Abl fusion protein. In normal cells, c-Abl is found in the nucleus as a negative regulator of cell growth, while BCR-Abl behaves as a fully cytoplasmic intrinsically active Tyr-kinase, giving rise to the development of this cancer. Recently, a very potent and selective inhibitor of BCR-Abl, Gleevec (or Glivec or STI-571 or CPG 57148B), a phenylamino-pyrimidine derivative, has come into the market in the treatment of CML, with very low or even null side effects. An important step in the comprehension of the mechanism of inhibition has been the elucidation of the crystal structure of the Abl domain in complex with STI-571.

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