Anaplastic lymphoma kinase as a therapeutic target in anaplastic large cell lymphoma, non-small cell lung cancer and neuroblastoma.
Anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase in the insulin receptor superfamily, was originally identified as the oncogenic NPM (nucleophosmin)-ALK fusion protein due to a t (2;5) chromosomal translocation in anaplastic large cell lymphomas. Many other chromosomal rearrangements or gene mutations/amplification leading to enhanced ALK activity have subsequently been identified and characterized in a number of human cancer types. The recent reports of EML4 (echinoderm microtubule-associated protein-like 4)-ALK oncogenic proteins in non-small cell lung cancer (NSCLC) and the identification of ALK activating point mutations and gene amplification in neuroblastoma have indicated ALK as a potential major therapeutic target for human cancers. In this review, the role of oncogenic ALK in development of various human cancers is summarized and the efforts and progress of developing small molecule ALK inhibitors as potential cancer therapeutics are updated. Several small molecule ALK inhibitors from distinctive chemical scaffolds in either clinical or preclinical development stage are highlighted and profiled. The challenges and future directions of developing small molecule ALK inhibitors as cancer therapeutics are discussed.
Cheng
Mangeng
M
Worldwide Discovery Research, Cephalon Inc, West Chester, PA 19380, USA. mcheng@cephalon.com
Ott
Gregory R
GR
D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000627:therapeutic use; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D017728:Lymphoma, Large-Cell, Anaplastic / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D009447:Neuroblastoma / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D015514:Oncogene Proteins, Fusion; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases