A5063856888- Peroxisome Proliferator-Activated Receptors
- Retinoids in leukemia and cellular processes
- Estrogen and related hormone effects
- Drug Transport and Resistance Mechanisms
- Adipose Tissue and Metabolism
- Liver Disease Diagnosis and Treatment
- Eating Disorders and Behaviors
- Eicosanoids and Hypertension Pharmacology
- Bioactive Compounds and Antitumor Agents
- Cancer, Lipids, and Metabolism
- Lipid metabolism and biosynthesis
- Synthesis and biological activity
- Cholesterol and Lipid Metabolism
- Nuclear Receptors and Signaling
- Circadian rhythm and melatonin
- Computational Drug Discovery Methods
- Synthesis and Reactions of Organic Compounds
- Receptor Mechanisms and Signaling
- Protein Degradation and Inhibitors
- Stress Responses and Cortisol
- Antioxidant Activity and Oxidative Stress
- Diet and metabolism studies
- Hepatitis C virus research
- Synthesis and Characterization of Pyrroles
- Metabolism, Diabetes, and Cancer
Goethe University Frankfurt
2016-2024
Ludwig-Maximilians-Universität München
1990
The lipid-sensing transcription factor PPARγ is the target of antidiabetic thiazolidinediones (TZD). At two sites within its ligand binding domain, it also binds oxidized vitamin E metabolites and mimetic garcinoic acid. While canonical interaction TZD site mediates classical activation, effects second on activity remain elusive. Here, we identified an agonist mimicking dual developed a selective site, unveiling potential noncanonical regulation activities. We found that this alternative...
The fatty acid sensing nuclear receptor families retinoid X receptors (RXRs) and peroxisome proliferator-activated (PPARs) hold therapeutic potential in neurodegeneration. Valuable pleiotropic activities of Wy14,643 models such conditions exceed its known PPAR agonistic profile. Here, we characterize the compound as an RXR agonist explaining effects report systematic structure–activity relationship analysis with discovery specific molecular determinants driving activity on PPARs RXRs. We...
Thyroid hormones (THs) operate numerous physiological processes through modulation of the nuclear thyroid hormone receptors and several other proteins. We report direct activation peroxisome proliferator-activated receptor gamma (PPARγ) retinoid X (RXR) by classical nonclassical THs as another molecular activity THs. The T4 metabolite TETRAC was most active TH on PPARγ with nanomolar potency binding affinity. demonstrate that promotes PPARγ/RXR signaling in cell-free, cellular, vivo...
Retinoid X receptors (RXRs, NR2B1–3) hold therapeutic potential in oncology, neurodegeneration, and metabolic diseases, but traditional RXR agonists mimicking the natural ligand 9-cis retinoic acid exhibit poor physicochemical properties, pharmacokinetics, safety profiles. Improved ligands are needed to exploit modulation as a promising concept various indications beyond its current role second-line cancer treatment. Here, we report co-crystal structure of complex with novel pyrimidine-based...
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) peroxisome proliferator-activated (PPAR) δ have been validated molecular targets to counter NASH. To achieve robust therapeutic efficacy in this multifactorial pathology, combined peripheral PPARδ-mediated activity effects FXR activation appear a promising multitarget approach. We...
The retinoid X receptor (RXR) is a ligand-sensing transcription factor acting mainly as universal heterodimer partner for other nuclear receptors. Despite presenting potential therapeutic target cancer and neurodegeneration, adverse effects typically observed RXR agonists, likely due to the lack of isoform selectivity, limit chemotherapeutic application currently available ligands. three human isoforms exhibit different expression patterns; however, they share high sequence similarity, major...
Abstract The bile acid activated transcription factor farnesoid X receptor (FXR) regulates numerous metabolic processes and is a rising target for the treatment of hepatic disorders. FXR agonists have revealed efficacy in treating non-alcoholic steatohepatitis (NASH), diabetes dyslipidemia. Here we characterize imatinib as first-in-class allosteric modulator report development an optimized descendant that markedly promotes agonist induced activation reporter gene assay expression HepG2...
Abstract Non-alcoholic steatohepatitis (NASH) - a hepatic manifestation of the metabolic syndrome is multifactorial disease with alarming global prevalence. It involves steatosis, inflammation and fibrosis in liver, thus demanding multiple modes action for robust therapeutic efficacy. Aiming to fuse complementary validated anti-NASH strategies single molecule, we have designed systematically optimized scaffold triple activation farnesoid X receptor (FXR), peroxisome proliferator-activated...
The nuclear retinoid X receptors (RXRs) are key ligand sensing transcription factors that serve as universal receptor heterodimer partners and thus involved in numerous physiological processes. Therapeutic targeting of RXRs holds high potential but available RXR activators suffer from limited safety. Selectivity for subtypes or certain heterodimers promising strategies safer modulation. Here, we report systematic structure-activity relationship studies on biphenyl carboxylates new chemotype....
Designed multitarget ligands are a popular approach to generating efficient and safe drugs, fragment-based strategies have been postulated as versatile avenue discover ligand leads. To systematically probe the potential of multiple discovery, we employed large fragment library for comprehensive screening on five targets chosen from proteins which successfully developed previously (soluble epoxide hydrolase, leukotriene A4 5-lipoxygenase, retinoid X receptor, farnesoid receptor). Differential...
Abstract Automated computational analogue design and scoring can speed up hit‐to‐lead optimization appears particularly promising in selective of side‐activities (SOSA) where possible diversity is confined. Probing this concept, we employed the cysteinyl leukotriene receptor 1 (CysLT R) antagonist cinalukast as lead for which discovered peroxisome proliferator‐activated α (PPARα) modulatory activity. We automatically generated a virtual library close analogues classified these roughly 8000...
Retinoid X receptors (RXR, NR2B1-3) hold therapeutic potential in oncology, neurodegeneration and metabolic diseases but traditional RXR agonists mimicking the natural ligand 9-cis retinoic acid exhibit poor physicochemical properties, pharmacokinetics safety profiles. Improved ligands are needed to exploit modulation as a promising concept various indications beyond its current role second-line cancer treatment. Here we report co-crystal structure of complex with novel pyrimidine-based...
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) retinoid X (RXR) activation by T4 metabolite TETRAC at nanomolar affinity. We demonstrate that is a highly active PPARγ agonist promoting signaling in cell-free, cellular vivo settings suggesting THs are activators of linking TH PPAR signaling.