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[Image: see text] The orphan nuclear receptor tailless homologue (TLX) is expressed almost exclusively in neural stem cells acting as an essential factor for their survival and is hence considered as a promising drug target in neurodegeneration. However, few studies have characterized the roles of TLX due to the lack of ligands and limited functional understanding. Here, we identify xanthines including caffeine and istradefylline as TLX modulators that counteract the receptor’s intrinsic repressor activity. Mutagenesis of residues lining a cavity within the TLX ligand binding domain altered the activity of these ligands, suggesting direct interactions with helix 5. Using xanthines as tool compounds, we observed a ligand-sensitive recruitment of the co-repressor silencing mediator for retinoid or thyroid-hormone receptors, TLX homodimerization, and heterodimerization with the retinoid X receptor. These protein–protein interactions evolve as factors that modulate the TLX function and suggest an unprecedented role of TLX in directly repressing other nuclear receptors.

Non-alcoholic steatohepatitis demands multiple modes of action for robust therapeutic efficacy. Here the authors design and optimize a triple modulator of farnesoid X receptor and peroxisome proliferator-activated receptors α and δ that counteracts hepatic inflammation and reverses hepatic fibrosis in mice.

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.

[Image: see text] 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.

CREBBP (CBP/KAT3A) and its paralogue EP300 (KAT3B) are lysine acetyltransferases (KATs) that are essential for human development. They each comprise 10 domains through which they interact with >400 proteins, making them important transcriptional co-activators and key nodes in the human protein-protein interactome. The bromodomains of CREBBP and EP300 enable the binding of acetylated lysine residues from histones and a number of other important proteins, including p53, p73, E2F, and GATA1. Here, we report a work to develop a high-affinity, small-molecule ligand for the CREBBP and EP300 bromodomains [(-)-OXFBD05] that shows >100-fold selectivity over a representative member of the BET bromodomains, BRD4(1). Cellular studies using this ligand demonstrate that the inhibition of the CREBBP/EP300 bromodomain in HCT116 colon cancer cells results in lowered levels of c-Myc and a reduction in H3K18 and H3K27 acetylation. In hypoxia (

The orphan nuclear receptor TLX is expressed almost exclusively in neural stem cells. TLX acts as an essential factor for neural stem cell survival and is hence considered as a promising drug target in neurodegeneration. However, few studies have characterized the roles of TLX due to a lack of ligands and limited functional understanding. Here, we identify caffeine and istradefylline as TLX ligands that counteract the receptor’s intrinsic repressor activity in reporter gene assays and modulate TLX regulated SIRT1 and p21 expression. Mutagenesis of residues lining a cavity within the TLX ligand binding domain altered activity of these ligands suggesting direct interactions with helix 5. Using istradefylline as a tool compound, we observed ligand-sensitive recruitment of the co-repressor SMRT and heterodimerization of TLX with RXR. Both protein-protein complexes evolve as factors that modulate TLX function and suggest an unprecedented role of TLX in directly repressing other nuclear receptors.

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.

Multitarget design offers access to bioactive small molecules with potentially superior efficacy and safety. Particularly multifactorial chronic inflammatory diseases demand multiple pharmacological interventions for stable treatment. By minor structural changes, we have developed a close analogue of the cysteinyl-leukotriene receptor antagonist zafirlukast that simultaneously inhibits soluble epoxide hydrolase and activates peroxisome proliferator-activated receptor g. The triple modulator exhibits robust anti-inflammatory activity in vivo and highlights the therapeutic potential of designed multitarget agents.

The nuclear farnesoid X receptor (FXR) and the enzyme soluble epoxide hydrolase (sEH) are validated molecular targets to treat metabolic disorders such as non‐alcoholic steatohepatitis (NASH). Their simultaneous modulation in vivo has demonstrated a triad of anti‐NASH effects and thus may generate synergistic efficacy. Here we report dual FXR activators/sEH inhibitors derived from the anti‐asthma drug Zafirlukast. Systematic structural optimization of the scaffold has produced favorable dual potency on FXR and sEH while depleting the original cysteinyl leukotriene receptor antagonism of the lead drug. The resulting polypharmacological activity profile holds promise in the treatment of liver‐related metabolic diseases., Changing targets: The anti‐asthma drug Zafirlukast was used as a lead to develop dual farnesoid X receptor activators/soluble epoxide hydrolase inhibitors. Systematic structural modification produced the desired polypharmacological profile and depleted the drug's original on‐target activity while conserving the favorable molecular scaffold. Optimized compounds engaged the desired targets in cellular settings. The designed multi‐target profile may generate synergies in treating liver‐related metabolic diseases.

[Image: see text] 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.

Thyroid hormones (THs) operate numerous physiological processes through the nuclear thyroid hormone receptors and several other proteins. Here we report direct peroxisome proliferator-activated receptor gamma (PPARγ) and retinoid X receptor (RXR) activation by the T4 metabolite TETRAC at nanomolar affinity. We demonstrate that TETRAC is a highly active PPARγ agonist promoting PPARγ signaling in cell-free, cellular and in vivo settings suggesting that TETRAC and other THs are activators of PPARγ linking TH and PPAR signaling.

As a cellular bile acid sensor, farnesoid X receptor (FXR) participates in regulation of bile acid, lipid and glucose homeostasis, and liver protection. Clinical results have validated FXR as therapeutic target in hepatic and metabolic diseases. To date, potent FXR agonists share a negatively ionizable function that might compromise their pharmacokinetic distribution and behavior. Here we report the development and characterization of a high-affinity FXR modulator not comprising an acidic residue.

In silico screening of DrugBank database to detect liver X receptor (LXR) agonism of marketed drugs using a self-organizing map and successive LXR-Gal4 hybrid reporter gene assay evaluation in vitro discovered alitretinoin and bexarotene as partial liver X receptor agonists. Dose-response curves demonstrated that plasma concentrations observed in clinical trials are sufficient for LXR activation and thus could account for LXR-mediated side-effects such as hypercholesterolemia and hyperlipidemia. The discovered drugs are the first reported dual LXR/RXR agonists and can serve as lead structures for LXR and dual LXR/RXR modulator development.

The accurate prediction of the strength of protein–ligand interactions is a very difficult problem despite impressive advances in the field of biomolecular modeling. There are good reasons to believe that quantum mechanical methods can help with this task, but the application of such methods in the context of scoring is still in its infancy. Here we benchmark several wave function theory (WFT), density functional theory (DFT) and semiempirical quantum mechanical (SQM) approaches against high-level theoretical references for realistic test cases. Based on our findings for systematically generated model systems of real protein/ligand complexes from the PDB-bind database, we can recommend SCS-MP2 and B2-PLYP-D3 as reference methods, TPSS-D3+Dabc/def-TZVPP as the best DFT approach and PM6-DH+ as a fast and accurate alternative to full ab initio treatments.