Structural modifications of the retinoid X receptor (RXR) selective compound 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2- naphthyl)ethenyl]benzoic acid (LGD1069), which is currently in phase I/IIA clinical trials for cancer and dermatological indications, have resulted in the identification of increasingly potent retinoids with > 1000-fold selectivity for the RXRs. This paper describes the design and preparation of a series of RXR selective retinoids as well as the biological data obtained from cotransfection and competitive binding assays which were used to evaluate their potency and selectivity. The most potent and selective of the analogs is 6-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2- yl)cyclopropyl]nicotinic acid (12d; LG100268). This compound has proven useful for investigating RXR dependent biological pathways including the induction of programmed cell death (PCD) and transglutaminase (TGase) activity. Our studies indicate that the induction of PCD and TGase in human leukemic myeloid cells is dependent upon activation of RXR-mediated pathways.

all-trans-Retinoic acid is known to bind to the retinoic acid receptors (RARs) resulting in an increase in their transcriptional activity. In contrast, recently identified 9-cis-retinoic acid (9-cis-RA), which is an additional endogenous RA isomer, is capable of binding to both RARs and retinoid X receptors (RXRs). These distinct properties have raised questions as to the biological role governed by these two retinoic acid isomers and the set of target genes that they regulate. Herein, we report the synthesis of high specific activity [3H]-9-cis-RA and its application to study the ligand-binding properties of the various retinoid receptor subtypes. We examined the binding properties of RARs and RXRs for a series of synthetic retinoids and compared the ligand-binding properties of these arotinoid analogs with their ability to regulate gene expression via the retinoid receptors in a cotransfection assay. The utilization of the [3H]-9-cis-RA competitive binding assay and the cotransfection assay has made it possible to rapidly identify important structural features of retinoids leading to increased selectivity for either the RAR or RXR receptor subtypes.

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