Tyrosine kinase inhibitors in cancer treatment (part II)

In the last few years, enormous progress in the field of signal transductio n inhibition has been made. Many companies have entered the field. Along wi th the epidermal growth factor receptor (EGFR) tyrosine kinase, many other tyrosine kinases have been identified as interesting targets for drug disco very projects. X-ray data of more than 40 crystal structures of protein a k inases, in most cases complexed with an inhibitor, have been published. Pha rmacophore models for the binding of inhibitors in the ATP-binding site of protein kinases have been developed that are generally applicable, enabling the rational design of tyrosine as well as serine/threonine kinase inhibit ors. It has been proven by numerous examples that the ATP-binding of protei n kinases is an exciting target for the design of anticancer drugs. In many cases, it has also been demonstrated that through rational design it is po ssible to modify a lead structure in such a way that inhibitors with an alt ered selectivity profile are obtained. Chemical optimisation of several lea d structures led to development candidates with potent in vitro and in vivo activity fulfilling the pharmacodynamic, pharmacokinetic, toxicological an d technical (synthesis, formulation) requirements for a clinical candidate. Currently, there are seven tyrosine kinase inhibitors in early phases of c linical trials. In addition, several candidates are close to entering Phase I trials this year or at the beginning of next year. It is expected that p ositive results from clinical trials will greatly contribute to the clinica l proof of concept of the value of signal transduction inhibition and will greatly stimulate further research in this area. This review is a continuat ion of a review with the same title of last year and summarises published p atent literature and related publications between 1997 and September 1998.