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

ABSTRACT

Introduction: TrkA/B/C receptor activation supports growth, survival, and differentiation of discrete neuronal populations during development, adult life, and ageing but also plays numerous roles in human disease onset and progression. Trk-specific inhibitors have therapeutic applications in cancer and pain and thus constitute a growing area of interest in oncology and neurology. There has been substantial growth in the number of structural classes of Trk inhibitors and the number of industrial entrants to the Trk inhibitor field over the past six years.

Areas covered: In Part II of this two-part review, the discussion of recent patent literature covering Trk family inhibitors is continued from Part I and clinical research with Trk inhibitors is considered.

Expert opinion: Trk has been molecularly targeted for over a decade resulting in the progressive evolution of structurally diversified Trk inhibitors arising from scaffold hopping and HTS efforts. Correspondingly, there have been a growing number of clinical investigations utilizing Trk inhibitors in recent years, with a particular focus on the treatment of NTRK-fusion positive cancers and chronic pain. The observed potential of Trk inhibitors to cause adverse CNS side effects however suggests the need for a more rigorous consideration of BBB permeation capabilities during drug development.

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

• Many novel Trk inhibitor scaffolds have been identified through HTS and repositioning of inhibitors developed for kinase targets other than Trk.

• Characterization of NTRK1/2/3 fusion oncogenic drivers as low frequency occurrences across multiple human cancer subtypes and the unambiguous clinical validation of the pan-Trk inhibitors entrectinib and LOXO-101 from phase I study reports in NTRK fusion-positive patients have enticed an increase in interest in Trk inhibitors.

• The potential for neurological side effects induced by CNS Trk inhibition is beginning to influence Trk inhibitor design with the inclusion of screening assays to assess BBB penetration and tailoring inhibitor design to reduce passive diffusion or increase efflux.

• Trk inhibitors are also gaining interest as modulators of the nervous system and are currently under clinical investigation for the treatment of osteoarthritis 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.