agn-194310 and 4-(2-(5-6-7-8-tetrahydro-5-5-8-8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic-acid

Novel synthetic antagonists of retinoic acid receptors (RARs) have been developed. To avoid interference by serum retinoids when testing these compounds, we established serum-free grown sub-lines (>3 years) of the prostate carcinoma lines LNCaP, PC3 and DU145. A high affinity pan-RAR antagonist (AGN194310, K(d) for binding to RARs = 2-5 nM) inhibited colony formation (by 50%) by all three lines at 16-34 nM, and led to a transient accumulation of flask-cultured cells in G1 followed by apoptosis. AGN194310 is 12-22 fold more potent than all-trans retinoic acid (ATRA) against cell lines and also more potent in inhibiting the growth of primary prostate carcinoma cells. PC3 and DU145 cells do not express RARbeta, and an antagonist with predominant activity at RARbeta and RARgamma (AGN194431) inhibited colony formation at concentrations (approximately 100 nM) commensurate with a K(d)value of 70 nM at RARgamma. An RARalpha antagonist (AGN194301) was less potent (IC(50) approximately 200 nM), but was more active than specific agonists of RARalpha and of betagamma. A component(s) of serum and of LNCaP-conditioned medium diminishes the activity of antagonists: this factor is not the most likely candidates IGF-1 and EGF. In vitro studies of RAR antagonists together with data from RAR-null mice lead to the hypothesis that RARgamma-regulated gene transcription is necessary for the survival and maintenance of prostate epithelium. The increased potencies of RAR antagonists, as compared with agonists, suggest that antagonists may be useful in the treatment of prostate carcinoma.

Topics: Antineoplastic Agents; Apoptosis; Benzoates; Cell Cycle; Humans; Male; Prostatic Neoplasms; Receptors, Retinoic Acid; Retinoids; Thiophenes; Tretinoin; Tumor Cells, Cultured

This article reports the synthesis and biological activity of new high affinity retinioic acid receptor (RAR) antagonists. The effect of introducing heteroatoms in the bicyclic ring system of the potent dihydronaphthalene RAR antagonist 8, and the variation of the pendant aromatic group on the ability of these compounds to function as RAR antagonists is discussed. The use of binding, transcriptional, and in vivo assays revealed that the 2,2-dimethylthiochromene analogue 59, and the 2,2-dimethylchromene derivative 85, were the most effective in blocking retinoid agonist induced activity.

Topics: Animals; Benzoates; Heterocyclic Compounds; Inhibitory Concentration 50; Naphthalenes; Receptors, Retinoic Acid; Recombinant Proteins; Retinoid X Receptors; Retinoids; Structure-Activity Relationship; Thiophenes; Transcription Factors; Transcription, Genetic