Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug

Chronic myelogenous leukaemia (CML) is a clonal haematological disorder that is characterized by a reciprocal translocation between chromosomes 9 and 22, and provided the first evidence of a specific genetic change associated with human cancer. The molecular consequence of this interchromosomal exchange is the creation of the BCR–ABL gene, which encodes a protein with elevated tyrosine-kinase activity. The demonstration that the creation of BCR–ABL is the molecular pathogenic event in CML provided the first potential drug target that clearly differed in its activity between normal and leukaemic cells. Importantly, BCR–ABL could be approached with classical tools of pharmacology, as its activity could clearly be described and measured in biochemical as well as cellular assays. Furthermore, cell lines derived from human leukaemic cells with the same chromosomal abnormality were available. A lead compound identified in a screen for inhibitors of protein kinase C was optimized to give a methyl-piperazine derivative that was originally named STI571 (imatinib, now known as Glivec or Gleevec), which was selected as the most promising candidate for clinical development. In in vitro screens against a panel of protein kinases, Glivec was found to inhibit the autophosphorylation of essentially three kinases: BCR–ABL, c-KIT and the platelet-derived growth factor (PDGF) receptor. Promising in vivo results — for example, with BCR–ABL-transformed cells in syngeneic mice — coupled with the facts that CML is essentially caused by a single molecular defect and that responses in CML can be measured easily using blood leukocyte count as the end point, led to CML being selected as the first indication for Phase I clinical testing of Glivec. The clinical development of Glivec was extremely rapid; the first patient was treated in June 1998, and less than three years later, on the basis of three large, multinational trials that showed Glivec to be safe and effective in all stages of CML, Glivec was approved by the FDA in May 2001. European and Japanese approval followed in November 2001. Current studies are investigating the activity of Glivec in cancers in which c-KIT and PDGF receptors might represent promising therapeutic targets. For example, gastrointestinal stromal tumours (GIST) are characterized by gain-of-function mutations in the KIT gene, and in February 2002, Glivec was approved by the FDA for the treatment of GIST. Chronic myelogenous leukaemia (CML) is a clonal haematological disorder that is characterized by a reciprocal translocation between chromosomes 9 and 22, and provided the first evidence of a specific genetic change associated with human cancer. The molecular consequence of this interchromosomal exchange is the creation of the BCR–ABL gene, which encodes a protein with elevated tyrosine-kinase activity. The demonstration that the creation of BCR–ABL is the molecular pathogenic event in CML provided the first potential drug target that clearly differed in its activity between normal and leukaemic cells. Importantly, BCR–ABL could be approached with classical tools of pharmacology, as its activity could clearly be described and measured in biochemical as well as cellular assays. Furthermore, cell lines derived from human leukaemic cells with the same chromosomal abnormality were available. A lead compound identified in a screen for inhibitors of protein kinase C was optimized to give a methyl-piperazine derivative that was originally named STI571 (imatinib, now known as Glivec or Gleevec), which was selected as the most promising candidate for clinical development. In in vitro screens against a panel of protein kinases, Glivec was found to inhibit the autophosphorylation of essentially three kinases: BCR–ABL, c-KIT and the platelet-derived growth factor (PDGF) receptor. Promising in vivo results — for example, with BCR–ABL-transformed cells in syngeneic mice — coupled with the facts that CML is essentially caused by a single molecular defect and that responses in CML can be measured easily using blood leukocyte count as the end point, led to CML being selected as the first indication for Phase I clinical testing of Glivec. The clinical development of Glivec was extremely rapid; the first patient was treated in June 1998, and less than three years later, on the basis of three large, multinational trials that showed Glivec to be safe and effective in all stages of CML, Glivec was approved by the FDA in May 2001. European and Japanese approval followed in November 2001. Current studies are investigating the activity of Glivec in cancers in which c-KIT and PDGF receptors might represent promising therapeutic targets. For example, gastrointestinal stromal tumours (GIST) are characterized by gain-of-function mutations in the KIT gene, and in February 2002, Glivec was approved by the FDA for the treatment of GIST.