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Desai, Harshada; Marathe, Megha; Potdar, Varada; Tiwari, Prabhakar; Joshi, Ashwini; Kadam, Sheetal R; Joshi, Arti Rajesh; Kulkarni, Abhay; Bhosale, Vikram; Hadambar, Avinash; Lodhiya, Bhavik; Udupa, Venkatesha; Behera, Dayanidhi; Chaudhari, Sachin S; Das, Sanjib; Bajpai, Malini; Gowda, Nagaraj; Iyer, Pravin S
Scientific reports, 05/2022, Volume: 12, Issue: 1Journal Article
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.
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