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.
Thyroid hormones (THs) operate numerous
physiological processes
through modulation of the nuclear thyroid hormone receptors and several
other proteins. We report direct activation of the nuclear peroxisome
proliferator-activated receptor gamma (PPARγ) and retinoid X
receptor (RXR) by classical and nonclassical THs as another molecular
activity of THs. The T4 metabolite TETRAC was the most active TH on
PPARγ with nanomolar potency and binding affinity. We demonstrate
that TETRAC promotes PPARγ/RXR signaling in cell-free, cellular,
and in vivo settings. Simultaneous activation of
the heterodimer partners PPARγ and RXR resulted in high dimer
activation efficacy. Compared to fatty acids as known natural ligands
of PPARγ and RXR, TETRAC differs markedly in its molecular structure
and the PPARγ-TETRAC complex revealed a distinctive binding
mode of the TH. Our observations suggest a potential connection of
TH and PPAR signaling through overlapping ligand recognition and may
hold implications for TH and PPAR pharmacology.
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.
As universal heterodimer partners of many nuclear receptors, the retinoid X receptors (RXRs) constitute key transcription factors. They regulate cell proliferation, differentiation, inflammation, and metabolic homeostasis and have recently been proposed as potential drug targets for neurodegenerative and inflammatory diseases. Owing to the hydrophobic nature of RXR ligand binding sites, available synthetic RXR ligands are lipophilic, and their structural diversity is limited. Here, we disclose the computer-assisted discovery of a novel RXR agonist chemotype and its systematic optimization toward potent RXR modulators. We have developed a nanomolar RXR agonist with high selectivity among nuclear receptors and superior physicochemical properties compared to classical rexinoids that appears suitable for in vivo applications and as lead for future RXR-targeting medicinal chemistry.
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