Retinoids, on interacting with their two nuclear retinoic acid and retinoid X receptor (RAR and RXR) classes, are able to inhibit breast cancer cell growth and proliferation and induce apoptosis (a process of programmed cell death). The pleiotropic effects of retinoids can also cause toxic side effects that will limit patient compliance. Therefore, new, more effective, less toxic retinoids need to be identified. Because of the diversity of the retinoid response which is modulated either directly or indirectly by the three subtypes in each retinoid receptor class and their isoforms, their ability to function as heterodimers, the response element variations in the promoter regions of genes to which the receptors bind, intermediary coactivators or corepressors, and the various receptor distribution patterns that vary with cell type and differentiation state the probability is high that more selective, less toxic retinoids for breast cancer treatment can be discovered, and then optimized. We have identified new classes of retinoids that inhibit breast cancer cell growth, including receptor subtype- selective retinoids, retinoid panagonists that mimic the activity of 9- cis-retinoic acid by binding and transcriptionally activating both RARs and RAXs, and apoptisis-inducing retinoids that act by a mechanism independent of the retinoid receptors. The goals of Project Retinoid Design and Synthesis, are the discovery and lead optimization of (1) potent, less toxic RAR/RXR panagonists; (2) improved RAR subtype-selective retinoids; (3) analogs of RARgamma-selective 6-[3-[(1-adamantyl)-4-hydroxyphenyl]-2- naphthalenecarboxylic acid (AHPN) that induce apoptosis in breast cancer cells but lack binding a affinity to the RARs so that retinoid toxic side effects are reduced; (4) improved retinoids that repress gene activation from AP-1 sites but do not induce transcription from retinoid response elements; and (5) synthesis of sufficient quantities of selected leads for evaluation at the molecular and cellular level and for subsequent evaluation against breast cancer xenograft growth and for pharmacologic/toxicologic studies in animal models. Optimum retinoids will be used as probes for studying the molecular mechanisms of retinoid action against breast cancer. Retinoid design will be guided by the results of these mechanistic studies and molecular assays to determine receptor selectivity for retinoid response element transcriptional activation or AP-1 site-induced transcriptional repression, couple with receptor binding affinity AHPN analog design will employ the parameters of apoptosis and WAF-1 induction, coupled with the absence of retinoid receptor binding or transcriptional activation. Computational analyses will be used to correlate bioassay results with retinoid structure to generate new leads and optimize them, as has been previously accomplished in current Project I by the design and synthesis of novel RXR-selective, RARgamma-selective, and anti-AP-1 retinoids.
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