Initiation, development and malignant progression of tumors depend on multiple genetic alterations as well as posttranscriptional and posttranslational modifications within the tumor cells. All these changes contribute to the loss of cell cycle control and to the evasion of programmed cell death. Along with the progression to the malignant phenotype, tumors develop a substantial cross-talk with the host tissue. This results in sustained angiogenesis and in tissue invasion leading finally to metastasis. Thus, the diverse collection of genetic alterations leading to oncogenes with dominant gain of function and to tumor suppressor genes with recessive loss of function manifest four essential alterations in cell physiology that collectively dictate malignant growth: loss of cell cycle control, escape from apoptosis, sustained angiogenesis and metastasis. Hallmarks of these processes are distinct changes in cellular and intercellular signalling. As our knowledge of the various signalling pathways increases, those critical steps within these pathways which are altered in tumor cells or stromal cells are being unravelled. The cumulative knowledge of these changes within the different tumor types will help us to identify specific targets for the development of novel cancer therapies.

In particular one class of signalling proteins—the protein kinases—has been identified to be involved in the deregulation of the four processes driving cancer progression. In late 2002 the human kinome, as the protein kinase family has been named, was reported to comprise 518 protein kinases. For quite some time it had been argued that because of the structural similarity of the kinase family members it would be rather unlikely to develop kinase selective inhibitors. However, the success story of Cleevec, an ABL tyrosine kinase inhibitor, and the approval of Iressa, an EGF receptor tyrosine kinase inhibitor, for the treatment of lung cancer, has convincingly demonstrated, that selective protein kinase inhibitors can be developed and are therapeutically effective.

A review will be given on protein kinase inhibitors, which are currently in clinical and preclinical development. The development of PTK787/ZK222584, an anti-angiogenic VEGF receptor tyrosine kinase inhibitor, will be described in some detail to trace the protein kinase inhibitor strategy from bench to bed-side.