Tropomyosin receptor kinase inhibitors: an updated patent review for 2010-2016 – Part I

ABSTRACT

Introduction: Tropomyosin receptor kinases (TrkA/B/C) play crucial roles in the development and maintenance of the nervous system, and aberrant expression of Trk has been implicated in neurological disorders as well as neural and non-neural neoplasms. Patent activity encompassing Trk inhibitors has grown substantially over the last 6 years, recognized by a rise in the number of pharmaceutical entrants to the field and the escalation of novel inhibitor chemotypes.

Area covered: In Part I of this two part review, a biological and structural overview of Trk is provided in the context of Trk as a therapeutic target for cancer and pain, followed by the report of recent patent literature claiming small molecule inhibitors of Trk family kinases or which describe inhibitors developed for other kinase targets but include noteworthy Trk inhibition/application. The discussion of the patent literature continues in Part II of this review, which includes an in-depth view of the current clinical applications of Trk inhibitors.

Expert opinion: Substantial synthetic efforts in Trk inhibitor development has propagated numerous and diverse inhibitor chemotypes, including TrkA-specific inhibitors. While many novel Trk inhibitors remain the original progeny of Trk-specific development programs, kinase inhibitors initially developed for other kinases have also been successfully repositioned for Trk.

KEYWORDS:

• Tropomyosin receptor kinase
• TrkA
• TrkB
• TrkC
• NTRK1/2/3
• tropomyosin receptor kinase inhibitor
• oncology
• cancer treatment
• chronic pain
• pruritis
• entrectinib
• LOXO-101
• targeted therapy

Article highlights

• As a mediator of growth factor signaling, dysregulation of Trk family kinases can have detrimental impacts on human health, most commonly in the form neurological disorders and cancer.

• There has been significant progress in the development and structural diversification of pan-tropomyosin receptor kinase (pan-Trk) inhibitors in recent years.

• Reports of recent crystallographic data of kinase-inhibitor complexes have allowed for the elucidation and validation of the diverse binding modes of inhibitors with Trk, including isoform-selective inhibitors.

• The structures of TrkA isoform-selective inhibitors disclosed by Array and Merck may offer unique advantages compared to first generation pan-Trk inhibitors in oncological applications or as anti-nociceptive agents for chronic pain.

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.

Additional information

Funding

This paper is not funded.