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A Novel Biphenyl-based Chemotype of Retinoid X Receptor Ligands Enables Subtype and Heterodimer Preferences
journal contribution
posted on 2019-08-20, 19:14 authored by Julius Pollinger, Simone Schierle, Leonie Gellrich, Julia Ohrndorf, Astrid Kaiser, Pascal Heitel, Apirat Chaikuad, Stefan Knapp, Daniel MerkThe nuclear retinoid
X receptors (RXRs) are key ligand sensing
transcription factors that serve as universal nuclear receptor heterodimer
partners and are thus involved in numerous physiological processes.
Therapeutic targeting of RXRs holds high potential but available RXR
activators suffer from limited safety. Selectivity for RXR subtypes
or for certain RXR heterodimers are promising strategies for safer
RXR modulation. Here, we report systematic structure–activity
relationship studies on biphenyl carboxylates as new RXR ligand chemotype.
We discovered specific structural modifications that enhance potency
on RXRs, govern subtype preference, and vary modulation of different
RXR heterodimers. Fusion of these structural motifs enabled specific
tuning of subtype preferential profiles with markedly improved potency.
Our results provide further evidence that RXR subtype selective ligands
can be designed and present a novel chemotype of RXR modulators that
can be tuned for subtype and heterodimer preferences.