Anaplastic lymphoma kinase inhibitors: an updated patent review (2014–2018)

ABSTRACT

Introduction: Anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase, has been discovered in several cancers, including anaplastic large-cell lymphoma, non-small cell lung cancer, and inflammatory myofibroblastic tumors. The deregulation of ALK activities, such as translocation and point mutation, results in human carcinogenesis. The use of ALK inhibitors in clinical cancer treatment has been shown to be efficacious, and the issue of resistance to ALK inhibitors has been reported. Consequently, the development of a new generation of ALK inhibitors is necessary.

Areas covered: This paper provides a comprehensive review of the patent literature from 2014 to 2018 including small molecule ALK inhibitors and their use as anticancer agents. The approved and developing ALK inhibitors are described.

Expert commentary: The available three generations of ALK inhibitors have shown a good anticancer effect in ALK-positive non-small cell lung cancer. An urgent issue in this field is ALK resistance development. The development of new ALK inhibitors through structure modification of currently available ALK inhibitors is proceeding, such as the synthesis of macrocyclic compounds. This article arranges the ALK inhibitors that have published in the patent in recent years. It may help in the investigation of a new generation of ALK inhibitors, which can overcome the resistance issue and development of novel drug candidates in the future.

KEYWORDS:

• Anaplastic lymphoma kinase
• cancer
• anaplastic large-cell non-Hodgkin’s lymphoma
• non-small cell lung cancer
• small molecule inhibitors

Article highlights

• ALK, a receptor tyrosine kinase, a subfamily of the insulin receptor family, is related to oncogenesis of human cancers in anaplastic large-cell lymphoma, non-small cell lung cancer, and inflammatory myofibroblastic tumors.

• The mechanisms of deregulation of ALK activity have been identified by gene fusion and point mutation results in the treatment of resistance of ALK inhibitors.

• To date, there are six approved ALK inhibitors, crizotinib, ceritinib, lectinib, brigatinib, lorlatinib, and entrectinib. ALL ALK inhibitors are approved for the treatment of non-small cell lung cancer.

• The development of small-molecule ALK inhibitors has accelerated in recent years. Among all the designed ALK inhibitors which have been reported in the patent literature, some possess strong inhibitory activity on ALK and/or mutant ALK and are effective against non-small cell lung cancer.

• The structure modification of approved ALK inhibitors and the investigation of targeting various targets agents have been developed vigorously in recent years. The optimization of designed compounds by use of the concept of macrocycle may provide a new insight to explore.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.