Members of the retinoid family have long been known to modulate cell metabolism, growth, differentiation, proliferation and apoptosis bringing this group of molecules to the forefront of oncology. Consequently over 30 naturally occurring and synthetic analogs of retinoic acid are now either in development or on the market for the treatment of cancer. Despite their potential, the therapeutic use of the retinoids has been limited by poor understanding of the cellular biology underlying their activity and of transcriptional control in general.

Our understanding of the complexities of transcription is however rapidly expanding and key targets for the treatment of cancer are therefore emerging. Histone deacetylase inhibitors represent one area of recent and massive growth. Likewise, the retinoic acids are going through a period of resurgence. Two areas of growth in this field can be identified. Most recently the body of data describing the growing family of co-regulatory molecules that confers gene specificity to retinoic acid occupancy has expanded dramatically. Building on this research, future developments are likely to involve the targeting of specific retinoic acid receptor/co-regulator systems that should lead to improved specificity and efficacy. This area forms one focus of our recent in depth analysis of the biology and pharmaceutical opportunities surrounding the retinoids. Another aspect of retinoid biology addressed in this report surrounds the retinoid receptors themselves. A surge in retinoid research in the early 1990’s culminated in the identification of the nuclear retinoid receptors. The pharmaceutical industry responded to this activity with the identification of receptor agonists suitable for further development. The surge in preclinical activity peaking in 1999 has now given way to clinical development. Current efforts are being placed on improving the affinity of candidates for the retinoid receptors and optimizing the mix of activity against the different members of this receptor family. Of interest in this respect is recent research emerging from Ligand Pharmaceuticals describing a series of novel cyclopropanyl methyl hexadienoic acid retinoids. These compounds exhibited either selective activity as RXR agonists or pan-agonists on one or more of each of the RAR and RXR isoforms. The most potent pan-agonist stimulated the RAR and RXR receptors with EC50 values of 17-59nM and 6-14nM respectively and showed good antiproliferative properties in multiple myeloma and cervical cancer cell lines.

Entry date January, 2003

Adapted from Farmer et al, Bioorg Med Chem Lett 2003 Jan 20;13(2):261-4 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.