The increased understanding of signal transduction pathways in normal and neoplastic cells has provided new strategies for therapeutic intervention in cancer (Hanahan and Weinberg 2000). Among the various signaling molecules, protein kinases have become an important group of drug targets, as these enzymes play a central role in diverse biological processes such as cell growth, differentiation, and apoptosis (Pawson and Nash 2000; Schlessinger 2000; Blume-Jensen and Hunter 2001; Manning et al. 2002). The recent development of specific kinase inhibitors blocking the activity of deregulated kinases appears to be sufficient to inhibit growth of tumors in vitro, in vivo, as well as in the clinic (Levitzki 1996; McMahon et al. 1998; Strawn and Shawver 1998; Matter 2001; Traxler et al. 2001).
The approach to design protein kinase inhibitors directed to the ATP binding site suffers from two major obstacles: access to the intracellular targets and selectivity. As there are more than 500 kinase in the human ge nome, the generation of inhibitors with an absolute specificity is unlikely to be achieved (Manning et al. 2002). The main emphasis, therefore, should be on inhibitors possessing a "reasonable" selectivity profile along with an "acceptable" side effect profile.
The recent discovery and development of STI571 (imatinib mesylate; Glivec; Gleevec; CGP57148), which was approved by the FDA on 10 May 2001 for the treatment of chronic myelogenous leukaemia (CML), shows that targeting the ATP binding of protein kinases for the treatment of various diseases is feasible.
Based upon its clear disease association in CML, the protein tyrosine kinase of Bcr-Abl, represents an ideal drug target to validate the clinical utility of protein kinase inhibitors as therapeutic agents (Daley et al. 1990; Gishizky et al. 1993; Gishizky 1996; Li et al. 1999). In fact, STI571 showed potent in vitro and in vivo antitumor activity in preclinical models that were selective not only for Bcr-Abl, but also for c-Kit and platelet-derived-growth factor receptor (PDGFR) kinases (Druker et al. 1996; Traxler et al 2001; Manley et al. 2002). Initially, clinical trials in CML and acute lymphoblastic leukaemia (ALL) demonstrated that STI571 is well tolerated and showed promising clinical responses (Druker et al. 2001; Kantarjian et al. 2002a,b; Sawyers et al. 2002; Talpaz et al. 2002; O'Brien et al. 2003). Later, clinical responses were reported for STI571 in diseases with deregulated PDGFR activity, like hypereosinophilic syndrome (HES) (Gleich et al. 2002; Cools et al. 2003a,b; Griffin et al. 2003), systemic mastocytosis (Pardanani et al. 2003), gastrointestinal stromal tumors (GIST) (Joensuu et al. 2001; Tuveson et al. 2001; VanOosterom et al. 2001; Heinrich et al. 2002, 2003a) and chronic myelogenous monocytic leukaemia (CMML) (Golub et al. 1994; Ross et al. 1998; Sjoblom et al. 1998; Magnusson et al. 2001; Schwaller et al. 2001; Steer and Cross 2002) or with deregulated c-Kit activity like GIST and/or in acute myelogenous leukaemia (AML) (Heinrich et al. 2002). Although STI571 showed impressive responses in chronic phase of CML, GIST, and HES, many advanced-stage patients develop drug resistance during treatment and subsequently relapse. Although the reasons for STI571 resistance in CML are multiple, mutations in the kinase domain appear to be the predominant mechanism (reviewed in Cowan-Jacob et al. 2004). Such resistance mechanisms might prove to be an issue for protein kinase inhibitors directed towards genetically unstable cells, and therefore a good understanding of this phenomenon is important for the development of new cancer therapies.
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