The fatty acid sensing nuclear receptor families retinoid X receptors (RXRs) and peroxisome proliferatoractivated receptors (PPARs) hold therapeutic potential in neurodegeneration. Valuable pleiotropic activities of Wy14,643 in models of such conditions exceed its known PPAR agonistic profile. Here, we characterize the compound as an RXR agonist explaining the pleiotropic effects and report its systematic structure−activity relationship analysis with the discovery of specific molecular determinants driving activity on PPARs and RXRs. We have designed close analogues of the drug comprising selective and dual agonism on RXRs and PPARs that may serve as superior pharmacological tools to study the role and interplay of the nuclear receptors in various pathologies. A systematically optimized high potency RXR agonist revealed activity in vivo and active concentrations in brain. With its lack of RXR/liver X receptor-mediated side effects and superior profile compared to classical rexinoids, it establishes a new class of innovative RXR modulators to overcome key challenges in RXR targeting drug discovery.
The retinoid X receptors
(RXR) are ligand-activated transcription
factors involved in multiple regulatory networks as universal heterodimer
partners for nuclear receptors. Despite their high therapeutic potential
in many pathologies, targeting of RXR has only been exploited in cancer
treatment as the currently available RXR agonists suffer from exceptional
lipophilicity, poor pharmacokinetics (PK), and adverse effects. Aiming
to overcome the limitations and to provide improved RXR ligands, we
developed a new potent RXR ligand chemotype based on the nonsteroidal
anti-inflammatory drug oxaprozin. Systematic structure–activity
relationship analysis enabled structural optimization toward low nanomolar
potency similar to the well-established rexinoids. Cocrystal structures
of the most active derivatives demonstrated orthosteric binding, and in vivo profiling revealed superior PK properties compared
to current RXR agonists. The optimized compounds were highly selective
for RXR activation and induced RXR-regulated gene expression in native
cellular and in vivo settings suggesting them as
excellent chemical tools to further explore the therapeutic potential
of RXR.
The 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.
Nonalcoholic
steatohepatitis (NASH) is considered as severe hepatic
manifestation of the metabolic syndrome and has alarming global prevalence.
The ligand-activated transcription factors farnesoid X receptor (FXR)
and peroxisome proliferator-activated receptor (PPAR) δ have
been validated as molecular targets to counter NASH. To achieve robust
therapeutic efficacy in this multifactorial pathology, combined peripheral
PPARδ-mediated activity and hepatic effects of FXR activation
appear as a promising multitarget approach. We have designed a minimal
dual FXR/PPARδ activator scaffold by rational fusion of pharmacophores
derived from selective agonists. Our dual agonist lead compound exhibited
weak agonism on FXR and PPARδ and was structurally refined to
a potent and balanced FXR/PPARδ activator in a computer-aided
fashion. The resulting dual FXR/PPARδ modulator comprises high
selectivity over related nuclear receptors and activates the two target
transcription factors in native cellular settings.
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