{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["12(1)"],"submitter":["Desai H"],"funding":["Glenmark Pharmaceuticals"],"pubmed_abstract":["The role of RORγ as a transcription factor for Th17 cell differentiation and thereby regulation of IL-17 levels is well known. Increased RORγ expression along with IL-17A levels was observed in animal models, immune cells and BAL fluid of COPD patients. Increased IL-17A levels in severe COPD patients are positively correlated with decreased lung functions and increased severity symptoms and emphysema, supporting an urgency to develop novel therapies modulating IL-17 or RORγ for COPD treatment. We identified a potent RORγ inhibitor, PCCR-1 using hit to lead identification followed by extensive lead optimization by structure-activity relationship. PCCR-1 resulted in RORγ inhibition with a high degree of specificity in a biochemical assay, with > 300-fold selectivity over other isoforms of ROR. Our data suggest promising potency for IL-17A inhibition in human and canine PBMCs and mouse splenocytes with no significant impact on Th1 and Th2 cytokines. In vivo, PCCR-1 exhibited significant efficacy in the acute CS model with dose-dependent inhibition of the PD biomarkers that correlated well with the drug concentration in lung and BAL fluid, demonstrating an acceptable safety profile. This inhibitor effectively inhibited IL-17A release in whole blood and BALf samples from COPD patients. Overall, we identified a selective inhibitor of RORγ to pursue further development of novel scaffolds for COPD treatment."],"journal":["Scientific reports"],"pagination":["8744"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9130233"],"repository":["biostudies-literature"],"pubmed_title":["An inhibitor of RORγ for chronic pulmonary obstructive disease treatment."],"pmcid":["PMC9130233"],"pubmed_authors":["Desai H","Iyer PS","Potdar V","Das S","Kadam SR","Hadambar A","Tiwari P","Joshi A","Behera D","Kulkarni A","Joshi AR","Lodhiya B","Udupa V","Bajpai M","Gowda N","Marathe M","Chaudhari SS","Bhosale V"],"additional_accession":[]},"is_claimable":false,"name":"An inhibitor of RORγ for chronic pulmonary obstructive disease treatment.","description":"The role of RORγ as a transcription factor for Th17 cell differentiation and thereby regulation of IL-17 levels is well known. Increased RORγ expression along with IL-17A levels was observed in animal models, immune cells and BAL fluid of COPD patients. Increased IL-17A levels in severe COPD patients are positively correlated with decreased lung functions and increased severity symptoms and emphysema, supporting an urgency to develop novel therapies modulating IL-17 or RORγ for COPD treatment. We identified a potent RORγ inhibitor, PCCR-1 using hit to lead identification followed by extensive lead optimization by structure-activity relationship. PCCR-1 resulted in RORγ inhibition with a high degree of specificity in a biochemical assay, with > 300-fold selectivity over other isoforms of ROR. Our data suggest promising potency for IL-17A inhibition in human and canine PBMCs and mouse splenocytes with no significant impact on Th1 and Th2 cytokines. In vivo, PCCR-1 exhibited significant efficacy in the acute CS model with dose-dependent inhibition of the PD biomarkers that correlated well with the drug concentration in lung and BAL fluid, demonstrating an acceptable safety profile. This inhibitor effectively inhibited IL-17A release in whole blood and BALf samples from COPD patients. Overall, we identified a selective inhibitor of RORγ to pursue further development of novel scaffolds for COPD treatment.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 May","modification":"2026-05-09T23:38:34.334Z","creation":"2025-04-04T19:32:50.14Z"},"accession":"S-EPMC9130233","cross_references":{"pubmed":["35610240"],"doi":["10.1038/s41598-022-12251-z"]}}