Rexinoids

Rexinoids are a class of synthetic ligands that selectively activate retinoid X receptors (RXRs), which are nuclear receptors that regulate gene expression. RXRs form permissive heterodimers with a variety of other nuclear receptors, including retinoic acid receptors (RARs), peroxisome proliferator-activated receptors (PPARs), liver X receptors (LXRs), and vitamin D receptors (VDRs). Upon activation by rexinoids, RXR-containing complexes modulate transcription of genes involved in cell differentiation, proliferation, apoptosis, and metabolism, producing antiproliferative and pro-differentiation effects in many cell types.

The pharmacological rationale for rexinoids lies in their ability to influence multiple signaling pathways through RXR as a central node. This can lead to altered cell cycle control, enhanced differentiation, and programmed cell death in malignant cells, while also affecting inflammatory and metabolic processes. Because RXR partners with diverse receptors, rexinoid effects can be broad and context-dependent, which has driven both interest and caution in clinical development.

Bexarotene (Targretin) is the most well-known rexinoid and is approved for the treatment of cutaneous T-cell lymphoma (CTCL). Beyond CTCL, rexinoids have been investigated in various cancers and in metabolic and neurodegenerative conditions, often in combination with other therapies. Clinical results have been mixed, with some activity in certain cancers but limited overall success in others. Safety concerns common to rexinoids include hyperlipidemia and thyroid dysfunction, as well as potential liver toxicity and pancreatitis, necessitating careful monitoring during therapy.