دورية أكاديمية
Discovery and Development of NLRP3 Inhibitors Targeting the LRR Domain to Disrupt NLRP3-NEK7 Interaction for the Treatment of Rheumatoid Arthritis.
| العنوان: | Discovery and Development of NLRP3 Inhibitors Targeting the LRR Domain to Disrupt NLRP3-NEK7 Interaction for the Treatment of Rheumatoid Arthritis. |
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| المؤلفون: | Li BY; Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China., Li P; Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China., Wei LY; Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China., Zou J; Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China., Wang YH; Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China., You QD; Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China., Jiang C; Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China., Di B; Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China., Xu LL; Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.; Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China. |
| المصدر: | Journal of medicinal chemistry [J Med Chem] 2024 Jun 27; Vol. 67 (12), pp. 9869-9895. Date of Electronic Publication: 2024 Jun 18. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Washington Dc : American Chemical Society Original Publication: [Easton, Pa.] : American Chemical Society, [c1963- |
| مواضيع طبية MeSH: | NLR Family, Pyrin Domain-Containing 3 Protein*/antagonists & inhibitors , NLR Family, Pyrin Domain-Containing 3 Protein*/metabolism , NIMA-Related Kinases*/antagonists & inhibitors , NIMA-Related Kinases*/metabolism , Arthritis, Rheumatoid*/drug therapy , Arthritis, Rheumatoid*/metabolism , Arthritis, Experimental*/drug therapy, Animals ; Humans ; Rats ; Drug Discovery ; Structure-Activity Relationship ; Male ; Inflammasomes/metabolism ; Inflammasomes/antagonists & inhibitors ; Molecular Docking Simulation ; Antirheumatic Agents/pharmacology ; Antirheumatic Agents/chemistry ; Antirheumatic Agents/chemical synthesis ; Antirheumatic Agents/therapeutic use |
| مستخلص: | Rheumatoid arthritis (RA) is a chronic autoimmune disease. Targeting NLRP3 inflammasome, specifically its interaction with NEK7 via the LRR domain of NLRP3, is a promising therapeutic strategy. Our research aimed to disrupt this interaction by focusing on the LRR domain. Through virtual screening, we identified five compounds with potent anti-inflammatory effects and ideal LRR binding affinity. Lead compound C878-1943 underwent structural optimization, yielding pyridoimidazole derivatives with different anti-inflammatory activities. Compound I-19 from the initial series effectively inhibited caspase-1 and IL-1β release in an adjuvant-induced arthritis (AIA) rat model, significantly reducing joint swelling and spleen/thymus indices. To further enhance potency and extend in vivo half-life, a second series including II-8 was developed, demonstrating superior efficacy and longer half-life. Both I-19 and II-8 bind to the LRR domain, inhibiting NLRP3 inflammasome activation. These findings introduce novel small molecule inhibitors targeting the LRR domain of NLRP3 protein and disrupt NLRP3-NEK7 interaction, offering a novel approach for RA treatment. |
| المشرفين على المادة: | 0 (NLR Family, Pyrin Domain-Containing 3 Protein) EC 2.7.11.1 (NIMA-Related Kinases) EC 2.7.11.1 (NEK7 protein, human) 0 (NLRP3 protein, human) 0 (Inflammasomes) 0 (Antirheumatic Agents) |
| تواريخ الأحداث: | Date Created: 20240618 Date Completed: 20240627 Latest Revision: 20240709 |
| رمز التحديث: | 20240709 |
| DOI: | 10.1021/acs.jmedchem.3c02407 |
| PMID: | 38888047 |
| قاعدة البيانات: | MEDLINE |
Find this issue from the American Chemical Society | تدمد: | 1520-4804 |
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| DOI: | 10.1021/acs.jmedchem.3c02407 |