SR1001 / Scripps Research Institute - LARVOL DELTA

Blockade of interleukin-17A contributes to a novel mechanism by which casticin relieves chronic migraine. (PubMed, J Ethnopharmacol) - "Casticin alleviated pain sensitization and CM-like symptoms in CM rats by targeting IL-17-mediated microglial polarization and glycolysis via inhibition of the PKM2-STAT3/NF-κB axis, which explains the mechanism by which Casticin relieves CM."

Journal • CNS Disorders • Migraine • Pain • IL17A • PKM • STAT3

Thymic Bmi-1 hampers γδT17 generation and its derived RORγt-IL-17A signaling to delay cardiac aging. (PubMed, Proc Natl Acad Sci U S A) - "The RORγt inhibitor SR1001 and IL-17A neutralizing antibody ixekizumab prevented thymic RORγt-IL-17A-dependent SA-PCH. Furthermore, RORγt bound to Bmi-1 through ARG237 and to RING1B through GLU235, which could be used as a therapeutic strategy for SA-PCH to construct binding peptides promoting Bmi-1-RING1B binding to RORγt and degrading RORγt for inhibiting γδT17 cell differentiation and IL-17A production. Thus, thymic Bmi-1 prevented IL-17A-dependent SA-PCH by decreasing γδT17 cell numbers."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Targeted Protein Degradation • BMI1 • IKZF1 • IL17A

IL-17 enhanced the susceptibility to fluoxetine resistance in depression via the JAK1-STAT6 signaling pathway. (PubMed, Int Immunopharmacol) - "The inhibition of Th17 differentiation and the reduction of peripheral IL-17 release could decrease sensitivity to fluoxetine resistance and relieve the depression-like behavior. This process might be associated with the JAK1-STAT6 pathway."

Journal • CNS Disorders • Depression • Mood Disorders • Psychiatry • IL17A • JAK1 • STAT6

The molecular circadian clock of eosinophils: A potential therapeutic target for asthma. (PubMed, Am J Physiol Cell Physiol) - "The therapeutic potential of the inverse ROR agonist SR1001 was evaluated in vitro and in a murine model of allergen-induced airway inflammation...This study suggests that clock proteins could serve as therapeutic targets in asthma. Pharmacological inhibition of ROR signaling demonstrated significant anti-inflammatory and bronchoprotective properties, indicating its potential as a novel treatment strategy for asthma and other eosinophilic diseases."

Journal • Allergy • Asthma • Eosinophilia • Hematological Disorders • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • ARNTL • BMAL1

Exosomal miR-205-5p contributes to the immune liver injury induced by trichloroethylene: Pivotal role of RORα mediating M1 Kupffer cell polarization. (PubMed, Ecotoxicol Environ Saf) - "However, this alleviation was reversed by the RORα antagonist SR1001...In addition, pretreatment of mice with SR1078, a specific RORα agonist, effectively blocked M1 polarization of KCs and reduced the severity of TCE-induced liver injury. Our study uncovers that miR-205-5p regulates KC M1 polarization by targeting RORα in immune liver injury induced by TCE sensitization, providing new insight into the molecular mechanisms and new therapeutic targets for ODMLT."

Journal • Contact Dermatitis • Dermatitis • Dermatology • Hepatology • Immunology • Liver Failure • MIR205

The disrupted molecular circadian clock of monocytes and macrophages in allergic inflammation. (PubMed, Front Immunol) - "Overall, our data suggest an interaction between the molecular circadian clock and monocytes/macrophages effector function in inflammatory lung diseases. The use of SR1001 leads to inflammatory resolution in vitro and in vivo and represents a promising clock-based therapeutic approach for chronic pulmonary diseases such as asthma."

Journal • Asthma • Immunology • Inflammation • Pulmonary Disease • Respiratory Diseases • ARNTL • BMAL1

Electroacupuncture of scalp acupoint alleviates cerebral ischemic inflammatory injury by down-regulating RORγt and promoting balance of IL-17A+Th17/FOXP3+Treg in MCAO rats. (PubMed, Zhen Ci Yan Jiu) - "EA of scalp acupoint MS6 can effectively improve the neurological function, behavior reaction and reduce cerebral infarct volume in ischemic stroke rats, which may be associated with its functions in down-regulating the expression of RORγt and promoting the balance of IL-17A+Th17/FOXP3+Treg to alleviate inflammatory injury after ischemic stroke."

Journal • Preclinical • Cardiovascular • CNS Disorders • Ischemic stroke • FOXP3 • IL10 • IL17A • IL21 • IL6 • TGFB1

Fasudil and SR1001 synergistically protect against sepsis-associated pancreatic injury by inhibiting RhoA/ROCK pathway and Th17/IL-17 response. (PubMed, Heliyon) - "Lipopolysaccharide remarkably upregulated the differentiation of Th17 cells in vitro, which could be significantly downregulated by fasudil or SR1001, and further downregulated by their combination treatment. Taken together, the combination of fasudil with SR1001 has a synergistic effect on protecting against sepsis-associated pancreatic injury in C57BL/6 mice."

Journal • Hepatology • Infectious Disease • Septic Shock • IL17A • RHOA • STAT3

Myeloid cell specific deficiency of RORα exacerbates choroidal neovascularization and subretinal inflammation in mice (ARVO 2023) - "Mouse monocyte/macrophage cells (RAW 264.7) were treated with synthetic RORα inverse agonists (SR3335 and SR1001) to assess lipid uptake and lipogenic gene expression in vitro...Layman Abstract (optional): Provide a 50-200 word description of your work that non-scientists can understand. Describe the big picture and the implications of your findings, not the study itself and the associated details."

Preclinical • Ophthalmology • Wet Age-related Macular Degeneration • PPARG

Treatment with butyrate alleviates dextran sulfate sodium and Clostridium difficile-induced colitis by preventing activity of Th17 cells via regulation of SIRT1/mTOR in mice. (PubMed, J Nutr Biochem) - "Besides, SR1001, an inhitor of the orphan nuclear receptors retinoic acid-related receptor γt (RORγt), which is a transcription factor specific to the formation of Th17 cells can suppress the Th17 development and alleviate the DSS +CD induced colitis in mice. Notably, the therapeutic effect of butyrate was revered when disease mice treated with butyrate and Ex-527, a SIRT1 inhibitor. Taken together, we demonstrate that butyrate alleviates dextran sulfate sodium and clostridium difficile induced colitis by preventing Th17 through activation of SIRT1/mTOR."

Journal • Preclinical • Gastroenterology • Gastrointestinal Disorder • Immunology • Infectious Disease • Inflammation • Inflammatory Bowel Disease • IL17A • IL1B • IL6 • TNFA

Chronic stress-induced depression requires the recruitment of peripheral Th17 cells into the brain. (PubMed, J Neuroinflammation) - "Our data demonstrated that inflammatory Th17 cells were pivotal in accelerating the onset and exacerbation of depressive symptoms in CRS-exposed rats. This subtype of CD4 T cells may be a promising therapeutic target for the early treatment of stress-induced depression."

Journal • CNS Disorders • Depression • Immunology • Inflammation • Mental Retardation • Mood Disorders • Psychiatry • Solid Tumor • CD4

Melatonin relieves Th17/CD4CD8 T cells inflammatory responses via nuclear-receptor dependent manner in peripheral blood of primary Sjögren's syndrome. (PubMed, Int Immunopharmacol) - "Melatonin relieved the inflammatory responses of Th17 and DN T cells in PBMCs from pSS patients in a nuclear receptors-dependent manner,suggesting that melatonin might be beneficial to pSS."

Journal • Immunology • Inflammation • Sjogren's Syndrome

Integrative analysis reveals clinically relevant molecular fingerprints in pancreatic cancer. (PubMed, Mol Ther Nucleic Acids) - "Further integrative analysis revealed that temozolomide and NVP-TAE684 showed higher sensitivity in the C1 subgroup, whereas the C2 cell lines were more sensitive to SR1001 and SRT-1720. Our results also showed that PCCLs with mutations in CDKN2A, TP53, and SMAD4 were more sensitive to certain anti-cancer drugs. Our integrative analysis identified molecular features of pancreatic cancer that were associated with clinical significance and drug sensitivity, providing potentially effective strategies for precision treatments of patients with pancreatic cancer."

Clinical • Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • CD4 • CDKN2A • SMAD4 • TP53

RORγt inhibitor SR1001 alleviates acute pancreatitis by suppressing pancreatic IL-17-producing Th17 and γδ-T cells in mice with ceruletide-induced pancreatitis. (PubMed, Basic Clin Pharmacol Toxicol) - "Collectively, these results showed that SR1001 exerted therapeutic effects on AP by suppressing IL-17-secreting Th17 and γδ T cells in the pancreas. Thus, SR1001 may be a promising drug for the treatment of AP in the clinic."

Journal • Preclinical • Pancreatitis • IL17A • IL6 • TNFA

Blockade of T helper 17 cell function ameliorates recurrent Clostridioides difficile infection in mice. (PubMed, Acta Biochim Biophys Sin (Shanghai)) - "Treatment with RORγt small molecule inhibitor SR1001 increased the expression of occludin, decreased the apoptotic rate of HCT-116 cells, and decreased the concentrations of Th17 and IL-17. Concisely, Th17 and IL-17 are potential indicators of RCDI and may serve as therapeutic targets for RCDI treatment. This study lays the foundation for future research on RCDI diagnosis and treatment."

Journal • Preclinical • Gastrointestinal Disorder • Infectious Disease • Inflammation • IL17A • PCR

Protective effects of resveratrol and SR1001 on hypoxia-induced pulmonary hypertension in rats. (PubMed, Clin Exp Hypertens) - "The mono-prevention with resveratrol or SR1001 significantly inhibited the Th17 cells differentiation, p-STAT3, p-MYPY1, RhoA, and GEF-H1 protein expression, which was further inhibited by their combination prevention. The combination of resveratrol and SR1001 has a synergistic interaction, suggesting that combined use of these pharmacological targets may be an alternative to exert further beneficial effects on HPH."

Journal • Preclinical • Hypertension • Pulmonary Arterial Hypertension

Assessing the Selectivity of FXR, LXRs, CAR, and RORγ Pharmaceutical Ligands With Reporter Cell Lines. (PubMed, Front Pharmacol) - "Secondly, we finely characterized the activities of commercially available FXR, LXRα, LXRβ, CAR, RORγ, and PXR agonists/antagonists GW4064, feraxamine, DY268, T0901317, GW3965, WAY252623, SR9238, SR9243, GSK2033, CITCO, CINPA1, PK11195, S07662, SR1078, SR0987, SR1001, SR2211, XY018, clotrimazole, dabrafenib, SR12813, and SPA70, respectively. Finally, although PXR was quite selectively activated or antagonized by its own ligands, it responded to several NRs ligands as well. Thus, using these reporter cell lines enabled us to precisely characterize the selectivity of pharmaceutical ligands for different nuclear receptors."

Journal • Preclinical

White light emitting diode induces autophagy in hippocampal neuron cells through GSK-3-mediated GR and RORα pathways. (PubMed, Aging (Albany NY)) - "SR1001, a specific inhibitor of RORα, protected the cells from light-induced activation of autophagy...GR inhibitor RU486 prevented light-induced up-regulation of RORα and the activation of autophagy...Furthermore, GSK-3 was identified as an upstream regulator of GR/RORα signaling as it was not affected by GR or RORα inhibitors. Taken together, our data demonstrate that GSK-3-mediated GR/RORα signaling pathway is involved in white LED light-induced autophagy in hippocampal neuron cells."

Journal • Ophthalmology

RORγt Inhibitor-SR1001 Halts Retinal Inflammation, Capillary Degeneration, and the Progression of Diabetic Retinopathy. (PubMed, Int J Mol Sci) - "Finally, when a RORγt small molecule inhibitor (SR1001) was subcutaneously injected into diabetic mice, retinal inflammation and capillary degeneration were ameliorated. These findings establish a pathologic role for RORγt in the onset of diabetic retinopathy and identify a potentially novel therapeutic for this blinding disease."

Journal • Diabetes • Diabetic Macular Edema • Diabetic Retinopathy • Immunology • Metabolic Disorders • Ophthalmology • Retinal Disorders • IL17A

Melatonin inhibits apoptosis in mouse Leydig cells via the retinoic acid-related orphan nuclear receptor α/p53 pathway. (PubMed, Life Sci) - "However, the RORα inhibitor SR1001 reversed the inhibitory effects of melatonin on apoptosis (P < 0.05)...p53 reversed the anti-apoptotic process involving RORα-mediated melatonin in mouse Leydig cells. Collectively, our findings suggested that melatonin inhibited apoptosis via the RORα/p53 pathway."

IO Biomarker • Journal • Preclinical • Review

Development of zebrafish demyelination model for evaluation of remyelination compounds and RORγt inhibitors. (PubMed, J Pharmacol Toxicol Methods) - "Both GSK805 and SR1001 markedly recovered EB-induced axon and motor neuron damage, and exhibited significantly inhibitory effects of neutrophil infiltration and macrophage recruitment. These results indicate that EB treatment can induce zebrafish demyelination; and the zebrafish demyelination model in combination with quantitative motility and myelin assays is a predictive, reproducible and relatively high throughput screening for rapidly in vivo identification of remyelination compounds and RORγt inhibitors."

Journal

Roles of Histone Acetyltransferases CBP/p300 and Transcriptional Factor RORα/REV-ERBα Against TNFα-induced CCL2 Expression in RA-FLSs (ACR-ARHP 2019) - " To examine the effect of RORα antagonist SR1001 and REV-ERBα agonist GSK4112 on TNFα-induced CCL2 expression, primary cultured RA-FLSs were treated with SR1001 (20μM) and/or GSK4112 (20μM) in the presence of TNFα (10ng/ml) for 24h... We newly found that TNFα induced expression of CCL2 through RORα and REV-ERBα, which was associated with CBP/p300 in RA-FLSs, in the same manner as Bmal1. Results propose these molecules as novel therapeutic targets of RA. Figure 1 Figure 1."

The role of RORα in salivary gland lesions in patients with primary Sjögren's syndrome. (PubMed, Arthritis Res Ther) - "Our data reveal the importance of RORα in controlling pathologic lymphocytic infiltration of the salivary glands and suggest that RORα may be a druggable target in treating pSS."

Clinical • Journal