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

Rongshi Li, Stephan W. Morris

Research output: Contribution to journalReview article

105 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)372-412
Number of pages41
JournalMedicinal Research Reviews
Volume28
Issue number3
DOIs
StatePublished - May 1 2008

Fingerprint

Molecules
Neoplasms
Therapeutics
Fusion reactions
Anaplastic Large-Cell Lymphoma
anaplastic lymphoma kinase
Tumors
Receptor Protein-Tyrosine Kinases
Human Development
Glioblastoma
Neuroblastoma
Sarcoma
Non-Hodgkin's Lymphoma
Carcinogenesis
Phosphotransferases
Chemical activation
Breast Neoplasms
Ligands
Growth

Keywords

  • Anaplastic large-cell lymphoma (ALCL)
  • Anaplastic lymphoma kinase (ALK)
  • Esophageal squamous cell carcinoma (esophageal SCC)
  • Inflammatory myofibroblastic tumor (IMT)
  • Midkine (MK)
  • Pleiotrophin (PTN)
  • Structure-based drug design
  • Tyrosine kinase inhibitors

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology
  • Drug Discovery

Cite this

Development of anaplastic lymphoma kinase (ALK) small-molecule inhibitors for cancer therapy. / Li, Rongshi; Morris, Stephan W.

In: Medicinal Research Reviews, Vol. 28, No. 3, 01.05.2008, p. 372-412.

Research output: Contribution to journalReview article

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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.",
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