Protein tyrosine kinase inhibitors in cancer treatment

Abstract

Competition in the field of tyrosine kinase inhibitors has increased in the last few years. New receptor and non-receptor tyrosine kinases have been identified as attractive targets for drug discovery programs. A pharmacophore model of the ATP-binding site of the epidermal growth factor-receptor (EGF-R) tyrosine kinase has been developed and successfully used for the rational design of tyrosine kinase inhibitors. Several inhibitor classes containing a phenylamino-pyrimidine moiety in their structure have provided highly selective ATP-competitive tyrosine kinase inhibitors, active in the low nanomolar or even picomolar range, thus proving that the ATP-binding site of tyrosine kinases is an attractive target for the design of anticancer drugs. More and more examples of inhibitors against several tyrosine kinases are being described which, in addition to showing potent and selective in vitro<> activity, exhibit potency in relevant cellular and in vivo models.<> Presently, several tyrosine kinase inhibitors with an interesting in vitro and in vivo profile are in preclinical evaluation and are expected to enter Phase I clinical trials later this year or early next year. This review summarises development of the last two years in the design and biological profiling of tyrosine kinase inhibitors with special focus on the phenylamino-pyrimidine-containing classes of compounds.