Action mechanism of retinoid-synergistic dibenzodiazepines.
4-[5H-2,3-(2,5-Dimethyl-2,5-hexano)-5-methyldibenzo[b,e][1,4 ]diazepin-11-yl]benzoic acid (HX600), as well as its oxa- (HX620) and thia- (HX630) analogs, enhanced the activity 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 transient transfections with a DR1-based reporter gene and synergized with RA-bound RAR alpha and RAR beta in inducing transcription from a DR5-based reporter. In addition, all three compounds at high concentrations acted as RAR pan-antagonists in stably transfected RAR "reporter cells." These efficient synergists bind only weakly with RXRs in vitro, suggesting that they are RXR-RAR heterodimer-selective activators. These HX retinoids exhibited dual functionality, since they affected signalling through both retinoid receptor families (RARs and RXRs).
Umemiya
H
H
Faculty of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Japan.
Kagechika
H
H
Fukasawa
H
H
Kawachi
E
E
Ebisawa
M
M
Hashimoto
Y
Y
Eisenmann
G
G
Erb
C
C
Pornon
A
A
Chambon
P
P
Gronemeyer
H
H
Shudo
K
K
D001565:Benzoates / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D003984:Dibenzazepines / Q000494:pharmacology*; D004357:Drug Synergism; D018922:HL-60 Cells; D006801:Humans; D018168:Receptors, Retinoic Acid / Q000187:drug effects; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D014157:Transcription Factors / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects
D001565:Benzoates; D003984:Dibenzazepines; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D014157:Transcription Factors; C061133:tamibarotene; C104181:HX 600