title: Inhibitors of the anaplastic lymphoma kinase.
abstract: BACKGROUND
  Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase normally expressed in the developing nervous tissue. Genetic alterations of ALK are associated with a number of cancers, including anaplastic large cell lymphoma (ALCL) and a subset of non-small cell lung cancer (NSCLC). Standard therapies for these diseases include surgery plus unspecific cytotoxic agents, with a low therapeutic window and significant treatment-associated systemic toxicity. A few small-molecule inhibitors of ALK kinase activity have been described in the recent years, some of which are currently undergoing clinical evaluation.
  
  
  METHODS
  Literature was searched for all ALK inhibitors that have entered clinical investigation, including published research articles and meeting abstracts. Data on pharmacokinetics, safety and efficacy of crizotinib, as well as preliminary clinical data for second-generation compounds, are reviewed. The issue of drug resistance is discussed.
  
  
  CONCLUSIONS
  Understanding the specific genetic aberration that causes cancer development and progression allows major advances in cancer therapy. Along the same way shown by imatinib in chronic myeloid leukemia, compounds that selectively target ALK are bringing a revolution in the treatment of ALK-positive tumors. Crizotinib has just been approved, and new more potent ALK inhibitors will shortly follow. These molecules represent another excellent proof-of-principle for targeted therapy.
authors.affiliation: University of Milano-Bicocca, Monza, Italy. luca.mologni@unimib.it
authors.forename: Luca
authors.initials: L
authors.lastname: Mologni
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D002986:Clinical Trials as Topic; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D017728:Lymphoma, Large-Cell, Anaplastic / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011720:Pyrazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases