An updated patent review of rearranged during transfection (RET) kinase inhibitors (2016–present)

ABSTRACT

Introduction

Rearranged during transfection (RET) is a transmembrane receptor tyrosine kinase. Aberrations in RET signaling due to mutations, gene fusions, or overexpression can lead to carcinomas. Six inhibitors have been approved for the treatment of RET-driven cancers: vandetanib, cabozantinib, lenvatinib, sorafenib, selpercatinib, and pralsetinib. Only selpercatinib and pralsetinib have been developed specifically for RET, while the remaining are multikinase inhibitors. Several other RET targeted candidates are under clinical development.

Areas covered

This review covers recent patent literature describing small molecules that are active against RET since 2016 till present.

Expert opinion

RET represents a major therapeutic target as its alterations occur in nearly 2% of all cancers. Recent approvals for RET targeted therapy have been developed specifically to target the RET oncogene. These approvals represent a paradigm shift from the last decade to now focus on the development of selective RET inhibitors rather than multikinase inhibitors. These newly approved RET inhibitors still have clinical issues with drug resistance. It is imperative that the next iteration of RET inhibitors are developed to block common treatment-resistant mutations. To accomplish this, RET inhibitors should be developed in concert with genomic profiling to ensure the most relevant clinical mutations are targeted.

KEYWORDS:

• RET
• RET/PTC
• non-small cell lung cancer
• thyroid cancer
• precision medicine
• selpercatinib
• pralsetinib
• oncogene
• kinase inhibitor

Article highlights

• Patents on RET inhibitors from 2016–present have been reviewed. The potential use of RET inhibitors in inflammatory disease has also been discussed.

• Six drugs have been approved for the treatment of RET-driven malignancies, with selpercatinib and pralsetinib receiving FDA approval in 2020. The clinical trial results for these two drugs have been discussed.

• A paradigm shift in the patent literature has occurred to now focus on developing selective RET inhibitors rather than pursuing multikinase inhibitors.

• Newly approved selective RET inhibitors exhibit issues with drug resistance that should be addressed with the next generation of RET inhibitors.

Acknowledgments

The figures were created with Biorender.com.

Declaration of interests

B Frett has ownership interests in Synactix Pharmaceuticals, Inc. and is an inventor on WO2015187818A1, a patent on RET inhibitors. 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.

Author contributions

B Acharya and B Frett contributed equally to the conception and writing of the manuscript.

Additional information

Funding

This work was supported by the National Institutes of General Medical Sciences (P20 GM109005).