Development of anaplastic lymphoma kinase (ALK) small-molecule inhibitors for cancer therapy

Med Res Rev. 2008 May;28(3):372-412. doi: 10.1002/med.20109.

Abstract

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) involved in the genesis of several human cancers; indeed, ALK was initially identified in constitutively activated and oncogenic fusion forms--the most common being nucleophosmin (NPM)-ALK--in a non-Hodgkin's lymphoma (NHL) known as anaplastic large-cell lymphoma (ALCL) and subsequent studies identified ALK fusions in the human sarcomas called inflammatory myofibroblastic tumors (IMTs). In addition, two recent reports have suggested that the ALK fusion, TPM4-ALK, may be involved in the genesis of a subset of esophageal squamous cell carcinomas. While the cause-effect relationship between ALK fusions and malignancies such as ALCL and IMT is very well established, more circumstantial links implicate the involvement of the full-length, normal ALK receptor in the genesis of additional malignancies including glioblastoma, neuroblastoma, breast cancer, and others; in these instances, ALK is believed to foster tumorigenesis following activation by autocrine and/or paracrine growth loops involving the reported ALK ligands, pleiotrophin (PTN) and midkine (MK). There are no currently available ALK small-molecule inhibitors approved for clinical cancer therapy; however, recognition of the variety of malignancies in which ALK may play a causative role has recently begun to prompt developmental efforts in this area. This review provides a succinct summary of normal ALK biology, the confirmed and putative roles of ALK fusions and the full-length ALK receptor in the development of human cancers, and efforts to target ALK using small-molecule kinase inhibitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Anaplastic Lymphoma Kinase
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / therapeutic use*
  • Carrier Proteins / metabolism
  • Cytokines / metabolism
  • Disease Models, Animal
  • Drug Design
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism*
  • Enzyme Inhibitors / therapeutic use*
  • Humans
  • Lymphoma, Large-Cell, Anaplastic / enzymology
  • Midkine
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology
  • Neoplasms / metabolism
  • Nuclear Proteins / metabolism
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism
  • Receptor Protein-Tyrosine Kinases
  • Small Molecule Libraries*

Substances

  • Antineoplastic Agents
  • Carrier Proteins
  • Cytokines
  • Enzyme Inhibitors
  • Nuclear Proteins
  • Oncogene Proteins, Fusion
  • Small Molecule Libraries
  • nucleophosmin
  • pleiotrophin
  • Midkine
  • ALK protein, human
  • Anaplastic Lymphoma Kinase
  • Protein-Tyrosine Kinases
  • Receptor Protein-Tyrosine Kinases