Tyrosine kinase inhibitors in cancer drug discovery

Alex Matter, M.D.

Novartis Pharma AG, 4002 Basel, Switzerland

Inhibition of signal transduction inhibition has become a viable and attractive avenue in biomedical cancer research based on the discovery of a large number of somatic mutations in many different types of cancer that lead to deregulated growth signal transduction and subsequent aberrant growth, invasion, tumor-derived angiogenesis and metastasis. Examples of such situations are a) the deregulated bcr-abl tyrosine kinase that is causally related to the occurrence of chronic myelogenous leukemia (CML), b) EGF receptor activation through constitutive activation or overexpression, as found e.g. in breast cancer and c) activation of VEGF receptors through VEGF secretion by tumor cells, leading to tumor angiogenesis. In these three situations it has been possible to fashion potent and selective tyrosine kinase inhibitors that inhibit the catalytic sites of these receptors thereby inhibiting tumor growth. These orally active and relatively well-tolerated compounds can be used in the clinics, either as single agents or in combination with established cytotoxic agents. GlivecTM (STI571), for instance, is an inhibitor of the bcr-abl kinase that is well-tolerated in animals and man leading to major hematologic responses in almost 100% of patients with interferon-resistant CML. PKI166, on the other hand, is a dual inhibitor of EGF receptor (HER 1) as well as erbB (HER 2) that is highly active inhibiting growth of EGF-receptor overexpressing tumors in animals and that has entered clinical trials as well. Lastly, PTK787, a potent inhibitor of VEGF-receptor 2 (KDR) is able to suppress tumor growth at fully tolerated doses via suppression of tumor angiogenesis and also this agent has entered clinical trials in tumor patients. These three examples outline our ability to fashion entirely new, efficacious and relatively well-tolerated anticancer agents that are based on recent discoveries of molecular epidemiology in human cancer.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Molecular Basis of Oncogenesis.