RET kinase inhibitors: a review of recent patents (2012–2015)

ABSTRACT

Introduction: Tyrosine kinases are involved in the control of several biological processes and have been recognized as hot spots of oncogenic transformation, thus representing a major therapeutic target. Dysregulated activation of RET kinase, either through point mutations or gene fusions, is accountable for a significant fraction of thyroid carcinomas, as well as a minor population of lung cancers. Two drugs are currently available for the treatment of medullary thyroid carcinoma and two additional compounds have been approved for differentiated thyroid carcinoma. Several other molecules are under preclinical and clinical evaluation.

Areas covered: This review covers the most recent patent literature (2012–2015) describing compounds with activity against the RET kinase, trying to catch a view of the next generation of potential anti-RET drugs.

Expert opinion: RET has been a focus of molecularly targeted efforts for over a decade. However, none of the drugs currently on the clinical stage were specifically developed to hit RET, which was rather an off-target. Besides, only two of four drugs have activity on metastatic medullary carcinoma. Therefore, there is still a need of additional, more potent and more specific RET inhibitors, which will hopefully emerge from the new generation of compounds disclosed in most recent patents.

KEYWORDS:

• RET
• RET/PTC
• thyroid cancer
• non-small cell lung cancer
• vandetanib
• precision medicine
• cabozantinib

Article highlights

• RET tyrosine kinase is a validated target in molecularly defined subsets of cancer

• Four FDA-approved drugs are currently available for RET-positive thyroid cancer therapy

• The identification of RET gene fusions in NSCLC and CRC will spur efforts towards the discovery of new generation RET inhibitors

• New patents specifically focused on the RET kinase show promising anti-RET activity of novel molecules with improved KDR selectivity

• This review is meant to provide a glimpse of the next wave of RET inhibitors

This box summarizes key points contained in the article.

Declaration of interest

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 apart from those disclosed.

Additional information

Funding

L Mologni receives a research grant from the Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR) (project n. 3/13 - D.M. 593/2000 art. 11). C Gambacorti-Passerini receives a research grant from the Associazione Italiana per la Ricerca sul Cancro (AIRC) (2013 IG-14249). P Goekjian receives a research grant from the Sixth Framework Programme (LSHB-CT-2004-503467). L Scapozza receives a research grant from the Seventh Framework Programme (278042 FP7-HEALTH) (project SADEL).