Type II & III inhibitors of tropomyosin receptor kinase (Trk): a 2020–2022 patent update

ABSTRACT

Introduction

The Trk family proteins are membrane-bound kinases predominantly expressed in neuronal tissues. Activated by neurotrophins, they regulate critical cellular processes through downstream signaling pathways. Dysregulation of Trk signaling can drive a range of diseases, making the design and study of Trk inhibitors a vital area of research. This review explores recent advances in the development of type II and III Trk inhibitors, with implications for various therapeutic applications.

Areas covered

Patents covering type II and III inhibitors targeting the Trk family are discussed as a complement of the previous review, Type I inhibitors of tropomyosin receptor kinase (Trk): a 2020–2022 patent update. Relevant patents were identified using the Web of Science database, Google, and Google Patents.

Expert opinion

While type II and III Trk inhibitor development has advanced more gradually compared to their type I counterparts, they hold significant promise in overcoming resistance mutations and achieving enhanced subtype selectivity – a critical factor in reducing adverse effects associated with pan-Trk inhibition. Recent interdisciplinary endeavors have marked substantial progress in the design of subtype selective Trk inhibitors, with impressive success heralded by the type III inhibitors. Notably, the emergence of mutant-selective Trk inhibitors introduces an intriguing dimension to the field, offering precise treatment possibilities.

KEYWORDS:

• Cancer treatment
• tropomyosin receptor kinase
• TrkA
• TrkB
• TrkC
• Trk inhibitor
• type II inhibitor
• type III inhibitor

Article highlights

• The repertoire of type II Trk inhibitors has diversified through the repurposing of off-target kinase inhibitors, providing potential candidates for treating Trk-related diseases.

• Type II inhibitors effectively manage resistance mutations and, in some cases, exhibit unexpected affinities for escape mutants, opening avenues for exploring mutant-selective therapies.

• Type III inhibitors demonstrate the highest level of selectivity, emphasizing the necessity to delve deeper into the allosteric pocket and juxtamembrane domain to enhance their selectivity.

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.

Author contributions

The manuscript was conceptualized by J Bailey, who also conducted the patent search and authored the patent review. P Iliev composed the introduction and prepared the figures, while C Jaworski authored the expert opinion. All authors actively participated in the editorial process, refining and enhancing the manuscript

Additional information

Funding

P. Iliev was funded through a UBC Andrew Nord Scholarship.