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The discovery of the genes responsible for the onset and progression of cancer in the 80’s was perceived as the beginning of a new era in cancer research and treatment. As soon as the first oncogenes and tumor suppressor genes were identified it was clear that they were masters in the management of the cell response to extracellular stimuli. Aberrant signaling mechanisms and the deregulated cellular clock were responsible for the appearance of cancer. Thus, signal transduction pathways and the cell cycle became the focus of most of the studies that aimed to revert the oncogenic phenotype. The rational behind was relatively simple and made many to believe that a cure for cancer was soon to be achieved. If cancer cells arise by mutations on specific genes that alter the enzymatic activity of normal proteins involved in signaling pathways and cell cycle regulation, specific inhibition of these elements would interfere with cancer progression. From then, many different approaches have been designed and attempted, almost as many as different types of tumors have been identified. Also, many disappointments have been harvested ever since. But constancy pays off, and twenty years later, the first real success of drug design against cancer seems to have arrived as the first clinical trials on the tyrosine kinase inhibitor imatinib mesylate (Glivec trade mark, Novartis Pharmaceuticals Corp, East Hanover, NJ; formerly STI571) are released 1-5 . This is good news for cancer researchers and clinicians that will return from desperation to hope, since previous efforts on similar themes to that of STI571 were largely unsuccessful. Take, if you wish, the inhibitors of the Farnesyl Tranferase as an example for the demonstration of such a disappointment. Originally Farnesyl Tranferase Inhibitors (FTIs) were thought as specific drugs that would prevent the activation of the Ras protein by interfering with its localization to the plasma membrane. Ras is the most important oncogene involved in human cancer. Therefore its specific inhibition would imply a major breakthrough in cancer therapy. However, FTIs proved to be non-specific for Ras proteins. Furthermore, even though they showed some antitumoral activity in preclinical studies, its target seems to be independent on the status of the Ras protein 6 . But FTIs is not the only case and many potential candidates to become specific drugs for cancer treatment have failed to be effective and never reached the clinic. STI571 is a 2-phenylaminopyridine derivative that functions as an ATP competitive inhibitor for a small set of tyrosine kinases. It was developed as a specific inhibitor for the PDGFR kinase, but shows also activity against other kinases, most remarkably the Abl, and Kit kinases. Thus, any tumor where PDGFR, Abl or Kit kinases are key players, were potential candidates for STI571 treatment. As with many other drugs designed similarly, STI571 proved to be effective in preclinical studies against cells derived from patients with Chronic Myeloid Leukemia (CML) 7-

Intelligent drug design come of age: STI571 as the start a of a new era in cancer research and treatment