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Retinoids : An A-Z guide to their biology, therape

Posted on: 28 Feb 03


Retinoids play a key role in differentiation, proliferation and apoptosis. As a result over 30 analogs of retinoic acid are now either in development or on the market. Retinoids in current use are eff

The retinoids play a key role in differentiation, proliferation and apoptosis and as a result over 30 naturally occurring and synthetic analogs of retinoic acid are now either in development or on the market. Retinoids in current use are effective in only a small number of cancers as well as acne and psoriasis. Extending this benefit to other types of cancer as well as newer indications such as diabetes and airway inflammation has represented a hurdle that will only be fully overcome by taking into account the biology of the retinoids. LeadDiscovery’s "Retinoids: An A-Z guide to their biology, therapeutic opportunities & pharmaceutical development" represents one of the most comprehensive insights into the retinoid field published in recent years. The aim of this report is to bring the reader up to date with advances in this area, pharmaceutical activity relating to retinoid development and strategies that will lead to the identification of improved retinoids.

Available retinoids are effective in treating acne and psoriasis. Likewise the retinoids are also beneficial in the treatment of acute promyelocytic leukemia, skin cancer, Kaposi's sarcoma and cutaneous T cell lymphoma. This has led to the launch of Ligand Pharmaceuticals' three marketed retinoids Tagretin gel, Tagretin capsules and Panretin which are indicated for T cell lymphoma or Kaposi's sarcoma. Although the incidence of these cancers is relatively low Ligand's retinoids generated sales of $57 million in 2002.

Although numerous cancers are associated with alterations in retinoid biology, clinical efficacy of retinoids has been limited - understanding why, and how this "resistance" can be overcome therefore represents a major goal in oncology. Meeting this goal will extend the therapeutic benefit of the retinoids to other major cancers as well as other newer indications for the retinoids such as diabetes and COPD. These advances would be attractive both clinically and commercially.

Early clinical studies and retinoid development commenced without an understanding of retinoid molecular biology. It is now clear that the actions of these molecules are, in almost all cases, via their nuclear receptors, whereby they are able to impinge on the expression of multiple genes. It is therefore not surprising that a "shotgun" approach to the retinoids has generally produced disappointing results in the clinic.

"Retinoids : An A-Z guide to their biology, therapeutic opportunities & pharmaceutical development" takes the reader on a journey through the various field of retinoid biology and is designed to offer an insight into how the retinoids confer specificity under physiological conditions; the pathophysiology of the retinoids; and pharmaceutical strategies that may increase the therapeutic benefits of the retinoids. In particular the report overviews

  • biochemical and cellular pathways controlling retinoid uptake
  • retinoid synthesis and metabolism
  • the biology of the various proteins that shuttle the retinoids from cell to cell and onwards to their site of action
  • the various retinoid nuclear receptor complexes, their ligands and their interaction with the genome
  • modulation of nuclear receptor-conferred control of transcription by co-repressors and co-activators
  • the role of the retinoids in the pathophysiology of cancer as well as animal and clinical data surrounding the therapeutic use of the retinoids
  • retinoids in development or on the market

One of the main focuses of this report is the regulation of gene expression by nuclear receptor dimers and how plasticity has evolved within this system. The RXR receptor has emerged as a key binding partner, forming dimers with RAR receptors as well as members of the other nuclear receptor families. Each dimer is able to bind a specific set of DNA response elements, and the multiplicity of isoforms and splice variants of each receptor introduces a basic level of plasticity. Therefore during the drug development process one is faced with the choice of advancing molecules with mixed or selective activity. Since a large number of receptor subtypes exist, it is possible to adopt the middle ground - for example, Allergan have developed Tazarotene, which was the first of a new generation of receptor-selective retinoids targeting RARb and RARg.

The make-up of a particular dimer not only determines which genes it can influence, but it also determines which of the many co-regulatory molecules it may bind. The large number of possible dimer/co-regulatory complexes adds a further level of plasticity, through what has been termed the "co-factor code". Challenges of the future will include the selection of gene targets and the identification of dimer-co-regulatory complex(es) that play a role in the control of these genes. This report provides a full inventory of known co-regulatory molecules. Advances in genomics are allowing gene expression profiles to be identified for particular disease states and gene targeting is already aiding the drug development process. It is now hoped that the identification of dimer/co-regulatory complexes able to regulate the expression of these target genes will soon become a common feature of therapeutic development.

In short this report offers an overview of the history, a full account of the present and a view into the future of the retinoids and their therapeutic potential.

Following an expansion of LeadDiscovery's PharmaceuticalSolutions service we are now able to provide expert advice on medicinal chemistry surrounding the development of retinoid ligands, chemical libraries of candidate modulators and screening services to assay such libraries. Consequently, this dossier like all of our dossiers not only offers a strategic insight into this field and an opportunity to expedite target selection but they can also be used as a platform from which to rapidly develop therapeutic candidates.

For further details and to access this dossier visit the following address:

Other reports of interest (click on title to access dossier):

Targeting endogenous inhibitors of apoptosis: Opportunities for the treatment of cancer, stroke and MS

Histone deacetylase inhibitors: Redefining pharmaceutical approaches to the treatment of cancer


Last updated on: 27/08/2010 11:40:18

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