ACTION MECHANISM OF RETINOID-SYNERGISTIC DIBENZODIAZEPINES

)-5-methyldibenzo-[b,e][1,4]diazepin-11-yl]benzoic acid (HX600), as we ll as its oxa- (HX620) and thia- (HX630) analogs, enhanced the activit y of retinoic acid and a receptor alpha (RAR alpha)-selective agonist Am80 in HL-60 cell differentiation assays. HX600 synergizes with Am80 by binding to, and transactivating through, the RXR subunit of the RXR -RAR heterodimer, HX600 exhibited RXR pan-agonist activity in transien t transfections with a DR1-based reporter gene and synergized with RA- bound RAR alpha and RAR beta in inducing transcription from a DR5-base d reporter. In addition, all three compounds at high concentrations ac ted as RAR pan-antagonists in stably transfected RAR ''reporter cells. '' These efficient synergists bind only weakly with RXRs in vitro, sug gesting that they are RXR-RAR hetero dimer-selective activators. These HX retinoids exhibited dual functionality, since they affected signal ling through both retinoid receptor families (RARs and RXRs). (C) 1997 Academic Press.