Drugs targeted against protein kinases

Current treatments for cancer (surgery, radiation and chemotherapy) are successful for early stage localised disease but have severe side effects. New treatments are needed to increase the cure rate and life expectancy of patients. With the discovery of oncogenes, tumour suppressor genes and an understanding of their role in the development of the malignant disease, a new era of therapy has begun. Cancer is a manifestation of deregulated signalling pathways that mediate cell growth and programmed cell death. Protein kinases are essential elements in these signalling pathways. In the US, Novartis launched Gleevec (imantinib, STI-571) in May 2001 as the first anticancer drug whose mechanism of action is kinase inhibition. In Phase I trials, 23/24 patients with chronic myelogenous leukaemia (CML) had complete remissions and the drug is relatively non-toxic. Herceptin (trastuzumab) is a monoclonal antibody (mAb) against a member of the growth factor receptor family (HER-2/neu) that was launched in 1998 by Genentech for the treatment of breast cancer. Trastuzumab has an excellent antitumour profile, particularly when used in combination with doxorubicin and paclitaxol. These drugs are pioneering the treatment of cancer based on the molecular understanding of the disease. Numerous drugs that target growth factor receptors and their signalling pathways are in advanced clinical trials. Herein, antibodies against receptors and small molecule inhibitors of kinases in signalling pathways will be summarised. Inter-disciplinary preclinical studies have identified chemicals that target specific kinases. We believe that clinical studies of these agents will yield new anticancer agents that target specific diseases and that are less toxic than current agents.