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

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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. © 2007 Wiley Periodicals, Inc. Med Res Rev, 28, No. 3, 372–412, 2008