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

ABSTRACT

Introduction

Trk inhibitors are significant in the realm of personalized medicine as they target specific genetic alterations, such as NTRK gene fusions, leading to improved treatment outcomes for cancer patients. By tailoring the treatment to the genetic characteristics of the tumor rather than the tumor type, Trk inhibitors offer the potential for more effective and precise therapies, resulting in enhanced response rates and prolonged survival for patients with NTRK fusion-positive cancers.

Areas covered

Patents covering type I inhibitors targeting the Trk family are discussed, building upon our prior review series on Trk inhibitors. Relevant patents were identified through the Web of Science database, Google, and Google Patents.

Expert opinion

The field of Trk inhibitors has evolved significantly, as reflected in the current patent literature, which emphasizes the selective structural refinement of clinical champions. Efforts now concentrate on enhancing efficacy against on-target resistance mechanisms, with modifications made to improve potency, reduce toxicity, and enhance pharmacokinetics. Combination therapies show potential to address off-target resistance mechanisms and improve treatment outcomes. Challenges remain in accurately diagnosing NTRK gene alterations and integrating screening into routine clinical practice. Trk inhibitors have surpassed their conventional role of inhibition and are now seeing new applications in radiopharmaceutical development and as molecular targeting agents.

KEYWORDS:

• entrectinib
• larotrectinib
• selitrectinib
• tropomyosin receptor kinase
• TrkA
• NTRK
• Trk inhibitor

Article highlights

• The current patent literature on type I Trk inhibitors demonstrates a clear shift from early screening efforts to lead optimization and follow-on innovation, underscoring the progression of the field.

• The discussed patents prioritize efficacy against Trk escape mutants, illustrating the importance of addressing drug resistance mechanisms in current Trk inhibitor design.

• Current patents concentrate on follow-on innovation, employing subtly modifications to lead Trk inhibitors to improve efficacy, reduce toxicity, and enhance pharmacokinetics and bioavailability, highlighting the drive for optimization in clinical translation.

• Libraries of Trk inhibitors are notably smaller and more structurally refined with many highly potent inhibitors, which can be attributed to the insights into binding modes gained from an abundance of co-crystal structures.

Declaration of interests

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

One reviewer received research funds from InnoCare Pharma and ERASCA and is also a consultant for ENTOS, Inc.

Author Contribution statement

J.J. Bailey conceptualized and wrote the manuscript, conducted the literature search, and prepared the figures. C. Jaworski and P. Iliev contributed their expert opinion. All authors edited the manuscript.

Additional information

Funding

This paper was not funded.