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Identification of Retinoids with Nuclear Receptor Subtype-selective Activities¹

Cancer Center, La Jolla Cancer Research Foundation, La Jolla, California 92037 [J. M. L., M. H., M. P.], and Life Sciences Division, SRI International, Menlo Park, California 94025 [M. I. D., P. D. H.]

Retinoic acid (RA) and its synthetic analogues, retinoids, have shown promising results in the prevention of epithelial carcinogenesis and in the treatment of acute promyelocytic leukemia and various proliferative skin disorders. Retinoid action on gene regulation is mediated by three distinct nuclear retinoic acid receptor subtypes, RA receptors , ß, and . The existence of multiple RA receptors has raised the possibility that receptor subtype-specific retinoids with reduced side effects can be developed. To analyze the activity of retinoids at the molecular level, we used a receptor activation assay. RA and 22 retinoids were compared on the three receptor subtypes. We found the receptor to be least sensitive to activation by RA and the receptor to be most sensitive. Compared with RA, one of the retinoids showed increased activity for the and ß receptors. Three retinoids revealed no gene activation activity and showed no antagonistic effects when assayed in the presence of RA. Surprisingly, several of the retinoids were efficient activators of the ß and receptors but poor activators or nonactivators of the receptor. Our data demonstrate that the three RA receptor subtypes have differential ligand activation specificities and that the design of receptor subtype-selective retinoids is possible.

¹ This work was supported in parts by NIH Grants DK35083 and CA50676 (M. P.) and 32428 (M. I. D.). J. M. L. and M. H. were supported by a fellowship from the Deutsche Forschungsgemeinschaft.

² To whom requests for reprints should be addressed, at La Jolla Cancer Research Foundation, 10901 North Torrey Pines Road, La Jolla, CA 92037.

Received 4/18/91. Accepted 7/ 9/91.

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