The discovery and development of imatinib, a new paradigm for small molecule targeted cancer therapy

MEDI 215

Ulrike B. Pfaar, ulrike.pfaar@novartis.com, Oncology, Novartis Pharma AG, WKL-4.90.1.32, Klybeckstr. 141, Basel, CH-4056, Switzerland
Imatinib (Gleevec™) is used as first-line treatment of chronic myeloid leukemia (CML) and for Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). Imatinib is a protein-tyrosine kinase inhibitor which potently inhibits the Abl tyrosine kinase activity of Bcr-Abl in vitro and in vivo. The discovery of imatinib, however, also provided insight into principal mechanisms of resistance occurring in accelerated or blast-crisis CML patients. This stimulated the tailored drug development of nilotinib and dasatinib for treatment of CML in imatinib-resistant patients. In addition, imatinib is a potent inhibitor of the receptor kinase for stem cell factor, c-Kit and of the platelet-derived growth factor receptor kinase (PDGF-R). As a consequence of these activities, Imatinib is also indicated for other indications such as the treatment of gastrointestinal stromal tumors GISTs driven by deregulated c-Kit signaling, and hypereosinophilic syndrome driven by deregulated PDGF-R signaling.