title: Crizotinib, a small-molecule dual inhibitor of the c-Met and ALK receptor tyrosine kinases.
abstract: Crizotinib (PF-02341066), under development by Pfizer, is an orally bioavailable, ATP-competitive, small-molecule inhibitor of the receptor tyrosine kinases (RTKs) c-Met (also known as hepatocyte growth factor receptor) and anaplastic lymphoma kinase (ALK), for the potential treatment of cancers dependent on these oncogenic kinases for growth and survival. Since the first published characterizations of crizotinib only a few years ago, the drug has been extensively validated as a highly specific inhibitor of c-Met and ALK among > 120 different RTKs surveyed. In preclinical tumor xenograft studies, crizotinib inhibited the growth and survival of cell lines dependent upon c-Met or ALK enzymatic activity. Crizotinib has been particularly effective against anaplastic large cell lymphoma and non-small cell lung cancer (NSCLC) cell lines that harbor ALK translocations resulting in expression of oncogenic ALK fusion proteins. During early-stage clinical testing, crizotinib was well tolerated and produced dramatic antitumor activity in patients with ALK-rearranged NSCLC. At the time of publication, an ongoing phase III clinical trial is comparing crizotinib with standard second-line chemotherapy in previously treated patients with NSCLC harboring ALK rearrangement, and a phase III trial comparing crizotinib with standard chemotherapy in the first-line setting in non-squamous lung cancer is planned. Thus, in the future, crizotinib is expected to become a highly used therapeutic for the treatment of ALK-rearranged tumors.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA. srodig@partners.org
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002986:Clinical Trials as Topic; D000077547:Crizotinib; D017277:Drug Approval; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases