دورية أكاديمية
أعرض في EDS

Discovery of a novel fibroblast activation protein (FAP) inhibitor, BR103354, with anti-diabetic and anti-steatotic effects.

التفاصيل البيبلوغرافية
العنوان: Discovery of a novel fibroblast activation protein (FAP) inhibitor, BR103354, with anti-diabetic and anti-steatotic effects.
المؤلفون: Cho JM; Innovative Drug Research Institute, Boryung Pharm. Co., Ltd, Danwon-gu, Ansan-si, Gyeonggi-do, 15425, South Korea.; Department of Pharmacology, College of Medicine, Gachon University, Incheon, 21999, South Korea., Yang EH; Innovative Drug Research Institute, Boryung Pharm. Co., Ltd, Danwon-gu, Ansan-si, Gyeonggi-do, 15425, South Korea., Quan W; Innovative Drug Research Institute, Boryung Pharm. Co., Ltd, Danwon-gu, Ansan-si, Gyeonggi-do, 15425, South Korea., Nam EH; Innovative Drug Research Institute, Boryung Pharm. Co., Ltd, Danwon-gu, Ansan-si, Gyeonggi-do, 15425, South Korea., Cheon HG; Department of Pharmacology, College of Medicine, Gachon University, Incheon, 21999, South Korea. hgcheon@gachon.ac.kr.
المصدر: Scientific reports [Sci Rep] 2020 Dec 04; Vol. 10 (1), pp. 21280. Date of Electronic Publication: 2020 Dec 04.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE
أسماء مطبوعة: Original Publication: London : Nature Publishing Group, copyright 2011-
مواضيع طبية MeSH: Fatty Liver/*drug therapy , Gelatinases/*antagonists & inhibitors , Glucose Metabolism Disorders/*drug therapy , Hypoglycemic Agents/*pharmacology , Membrane Proteins/*antagonists & inhibitors, 3T3-L1 Cells ; Adipocytes/drug effects ; Animals ; Drug Discovery ; Drug Evaluation, Preclinical ; Endopeptidases ; Macaca fascicularis ; Male ; Mice ; Mice, Inbred C57BL ; Rats, Sprague-Dawley ; Serine Endopeptidases
مستخلص: Fibroblast growth factor (FGF) 21 is a class of hepatokines that plays a protective role against obesity, insulin resistance, and liver damage. Despite this, protective effects of FGF21 in human appear to be minimal, possibly due to its proteolytic cleavage by the fibroblast activation protein (FAP). Here, we presented a novel FAP inhibitor, BR103354, and described its pharmacological activities as a potential therapeutic agent for the treatment of metabolic disorders. BR103354 inhibited FAP with an IC 50 value of 14 nM, showing high selectivity against dipeptidyl peptidase (DPP)-related enzymes and prolyl oligopeptidase (PREP). In differentiated 3T3/L1 adipocytes, the addition of FAP diminished hFGF21-induced Glut1 and phosphorylated levels of ERK, which were restored by BR103354. BR103354 exhibited good pharmacokinetic properties as evidenced by oral bioavailability of 48.4% and minimal hERG inhibition. Single co-administration of BR103354 with hFGF21 reduced nonfasting blood glucose concentrations, in association with increased intact form of hFGF21 in ob/ob mice. Additionally, chronic treatment of BR103354 for 4 weeks reduced nonfasting blood glucose concentrations with improved glucose tolerance and with reduced triglyceride (TG) content in liver of ob/ob mice. Consistently, BR103354 improved hepatic steatosis and fibrosis in a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD)-induced non-alcoholic steatohepatitis (NASH) mouse model. FAP inhibitory effects of BR103354 were confirmed in normal cynomolgus monkeys. Together, BR103354 acts as an effective FAP inhibitor in vitro and in vivo, thereby demonstrating its potential application as an anti-diabetic and anti-NASH agent.
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المشرفين على المادة: 0 (Hypoglycemic Agents)
0 (Membrane Proteins)
EC 3.4.- (Endopeptidases)
EC 3.4.21.- (Serine Endopeptidases)
EC 3.4.21.- (fibroblast activation protein alpha)
EC 3.4.24.- (Gelatinases)
تواريخ الأحداث: Date Created: 20201205 Date Completed: 20210329 Latest Revision: 20211204
رمز التحديث: 20240829
مُعرف محوري في PubMed: PMC7718273
DOI: 10.1038/s41598-020-77978-z
PMID: 33277568
قاعدة البيانات: MEDLINE
الوصف
تدمد:2045-2322
DOI:10.1038/s41598-020-77978-z