Therapeutic use of selective synthetic ligands for retinoic acid receptors: a patent review

ABSTRACT

Introduction: Differentiation therapy using all-trans retinoic acid (ATRA) revolutionised the treatment of acute promyelocytic leukaemia to such an extent that it is now one of the most curable types of leukaemia, with ATRA and anthracycline-based chemotherapy providing cure rates above 80%. Isotretinoin is used to treat chronic acne. Here, we examine the information described in recent patents and the extent to which new findings are influencing extending retinoid-based differentiation therapy to other cancers, as well as the development of new therapies for other disorders.

Areas covered: A search has been performed on the literature and worldwide patents filed during 2014 to the present time, focusing on synthetic agonists and antagonists of retinoic acid receptors and novel compositions for the delivery of these agents.

Expert opinion: New potential therapeutic applications have been described, including lung, breast and head and neck cancers, T cell lymphoma and neurodegenerative, metabolic, ophthalmic, muscle, and inflammatory disorders. Recent patents have described the means to maximise retinoid activity. Two decades of efforts to extend retinoid-based therapies have been disappointing and new synthetic retinoids, target diseases and modes of delivery may well resolve this long standing issue.

KEYWORDS:

• RARs
• RXRs
• retinoids
• therapy
• leukaemia
• skin diseases

Article highlights

• There are highly selective agonists for all three RAR subtypes and antagonists except for RARβ.

• The tissue distribution of RAR subtypes is variable and functional redundancy is not the case.

• New patents describe the prospects of extending ATRA-driven differentiation therapy of acute promyelocytic leukaemia to other cancers.

• New patents have examined the prospects of broadening the therapeutic uses of retinoids to neurodegenerative, metabolic, ophthalmic, muscle and inflammatory disorders.

• New drug composition and delivery methods are important to improving the efficacy of retinoids.

This box summarizes key points contained in the article.

Acknowledgment

We thank Dr M. Chodynski, Pharmaceutical Research Institute, Warsaw for kindly drawing the structures for Figure 1.

Declaration of interest

G Brown, E Marcinkowska, A Marchwicka and A Cunningham are participants within the Marie Curie Initial Training Network DECIDE (Decision-making within cells and differentiation entity therapies). A Cunningham gratefully acknowledges receipt of a Marie Curie Research Fellowship. A Cunningham is a Marie Curie Research Associate. 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

This project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no 315902. A Marchwicka is the recipient of the grant PRELUDIUM No 2013/11/N/NZ3/00197 from National Science Centre in Poland.