Investigational drugs in early phase clinical trials targeting thermotransient receptor potential (thermoTRP) channels

ABSTRACT

Introduction

Thermo transient receptor potential (thermoTRP) channels are some of the most intensely pursued therapeutic targets of the past decade. They are considered promising targets of numerous diseases including chronic pain and cancer. Modulators of these proteins, in particular TRPV1-4, TRPM8 and TRPA1, have reached clinical development, but none has been approved for clinical practice yet.

Areas covered

The therapeutic potential of targeting thermoTRP channels is discussed. The discussion is centered on our experience and on available data found in SciFinder, PubMed, and ClinicalTrials.gov database from the past decade. This review focuses on the therapeutic progress concerning this family of channels, including strategies to improve their therapeutic index for overcoming adverse effects.

Expert opinion

Although thermoTRPs are pivotal drug targets, translation to the clinic has faced two key problems, (i) unforeseen side effects in Phase I trials and, (ii) poor clinical efficacy in Phase II trials. Thus, there is a need for (i) an enhanced understanding of the physiological role of these channels in tissues and organs and (ii) the development of human-based pre-clinical models with higher clinical translation. Furthermore, progress in nanotechnology-based delivery strategies will positively impact thermoTRP human pharmacology.

KEYWORDS:

• Cancer
• clinical trials
• inflammation
• nociception
• pain
• thermoTRPs channels
• TRPV1-4
• TRPM8
• TRPA1

Article highlights

• ThermoTRPs ion channels are validated therapeutic targets for numerous diseases including chronic pain to cancer.

• Modulators of these proteins, in particular TRPV1-4, TRPM8 and TRPA1, have reached clinical development, but their safety and efficacy are still a main issue.

• Poor clinical translation of preclinical results has precluded the progress of thermoTRP channel modulators as therapeutics.

• The development of human-based preclinical models for thermoTRP dysfunction will enhance the clinical translation of drug candidates.

• Topical application of thermoTRP modulators for skin disorders appears as a therapeutic strategy devoid of unwanted side effects associated with systemic distribution.

This box summarizes the key points contained in the article.

Acknowledgments

We thank the support of AEI (grants RTI2018-097189-B-C2-1and RTC-2017-6507-1), with FEDER funds from EU “Una manera de hacer Europa” and UMH (grant PAR-2019).

Declaration of interest

AFC, AFM, and GFB are founders of the spin-off Antalgenics SL. AFM and AFC are inventors of WO20188206742 (A1) and WO2012032209 (A3) patents, and AFM is inventor of WO2008049945 (A1) and WO2010009892 (A2). The authors have no other competing interest to declare. The authors have no other 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 study was funded by Grants from AEI (MICIU) RTI2018-097189-B-C2-1 (to AFM and AFC), RTI2018-097189-C2-2 (to RGM), RTC-2017-6507-1 (to AFM), with FEDER funds from EU “Una manera de hacer Europa” and grants from the UMH, PAR2019 (to AFM) and CSIC, 201980E030 (to RGM).