Discovery of a “Gatekeeper” Antagonist that Blocks Entry Pathway to Retinoid X Receptors (RXRs) without Allosteric Ligand Inhibition in Permissive RXR Heterodimers

Retinoid X receptor (RXR) heterodimers
such as PPAR/RXR, LXR/RXR,
and FXR/RXR can be activated by RXR agonists alone and are therefore
designated as permissive. Similarly, existing RXR antagonists show
allosteric antagonism toward partner receptor agonists in these permissive
RXR heterodimers. Here, we show 1-(3-(2-ethoxyethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-(trifluoromethyl)-1H-benzo­[d]­imidazole-5-carboxylic acid (14, CBTF-EE) as the first RXR antagonist that does not show
allosteric inhibition in permissive RXR heterodimers. This compound
was designed based on the hypothesis that RXR antagonists that do
not induce conformational changes of RXR would not exhibit such allosteric
inhibition. CD spectra and X-ray co-crystallography of the complex
of 14 and the RXR ligand binding domain (LBD) confirmed
that 14 does not change the conformation of hRXR-LBD.
The X-ray structure analysis revealed that 14 binds at
the entrance of the ligand binding pocket (LBP), blocking access to
the LBP and thus serving as a “gatekeeper”.