Thyrotropin Receptor Antagonism by a Novel Small Molecule: Preclinical In Vitro Observations

对抗 体外 内科学 受体 药理学 小分子 化学 计算生物学 医学 生物 遗传学
作者
George J. Kahaly,Lisa A. Steiner,Miranda M.C. van der Lee,Tanja A.E. van Achterberg,Roel J. Arends,Willem F. J. Karstens,Tobias Weirauch,Jil Henseling,Lara Frommer,Jan Wolf,Augustine George
出处
期刊:Thyroid [Mary Ann Liebert, Inc.]
卷期号:33 (6): 732-742 被引量:3
标识
DOI:10.1089/thy.2022.0694
摘要

Background: Treatment of Graves' hyperthyroidism (GH) and Graves' orbitopathy (GO) is far from adequate, and hence, new substances that specifically target the autoantigens in GH/GO are warranted. This study determined the preclinical in vitro efficacy of SYD5115, a novel low-molecular-weight compound that inhibits the thyrotropin receptor (TSH-R). Methods: The TSH-R inhibiting capability of SYD5115 was tested through stimulation of wild-type and chimeric TSH-R expressed in Chinese hamster ovary (CHO) cells using two functional (stimulatory and blocking) cell-based TSH-R-Ab bioassays. TSH-R expressing human orbital fibroblasts, collected from GH+GO patients (GOF), were stimulated with the monoclonal antibody M22 or with stimulatory TSH-R-Ab (TSAb)-positive sera with cyclic adenosine monophosphate (cAMP) or hyaluronic acid (HA) release as readouts. The effect of SYD5115 on the viability of GOF was tested in 4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide and scratch cell growth assays. Results: SYD5115 significantly and dose dependently inhibited the TSH-R activation through M22 or TSAb-positive sera in all performed bioassays. Inhibition showed similar levels in the TSAb reporter bioassay and in the cAMP assay with GOF. The % inhibition and compound concentration showed a sigmoidal relationship, with all seven TSAb-positive sera markedly inhibited by SYD5115. An SYD5115 dose-dependent inhibition of M22 (10 ng/mL, 6 hours)-stimulated HA and/or cAMP-release from GOF was observed. Strong SYD5115-induced inhibitions of M22-stimulated cAMP production in GOF were registered with SYD5115 concentrations of 1 (p = 0.0029), 10 (p < 0.0001), 100 (p < 0.0001), 1,000 (p < 0.0001), and 10,000 (p < 0.0001) nM, respectively. SYD5115-induced inhibition of M22-stimulated HA production was noted with SYD5115 concentrations of 100 (p = 0.0392), 1000 (p = 0.0431), and 10,000 (p = 0.0245) nM, respectively. The inhibitory activity of SYD5115 was confirmed in a human osteosarcoma U2OS cell line stably expressing human TSH-R with cAMP as readout. SYD5115 induced 100% inhibition of the M22-induced cAMP levels with a potency of 193 nM. Compared with control, SYD5115 did neither impact the growth nor the migration of cultivated GOF. In addition, SYD5115 did not alter the viability of GOF. Conclusions: SYD5115 blocked M22- and TSAb-induced TSH-R activity with a nanomolar potency in TSH-R-overexpressed CHO cells as well as primary GOF, which demonstrates the ability of this small molecule to block TSH-R overactivity.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
1秒前
halabouqii完成签到,获得积分10
1秒前
李爱国应助满意采纳,获得10
2秒前
安然无恙应助平常的紫蓝采纳,获得10
2秒前
Inory007发布了新的文献求助10
3秒前
5秒前
5秒前
6秒前
zhan20200503完成签到,获得积分10
7秒前
这个文献你有么完成签到,获得积分10
8秒前
小二郎应助lan采纳,获得10
8秒前
李颜龙完成签到,获得积分10
10秒前
liangye2222发布了新的文献求助10
10秒前
与山发布了新的文献求助10
11秒前
11秒前
高手如林完成签到,获得积分10
12秒前
高铭泽完成签到,获得积分20
12秒前
Hengjian_Pu完成签到,获得积分10
12秒前
友好胜完成签到 ,获得积分10
12秒前
坦率白萱发布了新的文献求助10
13秒前
方翔应助林白采纳,获得100
13秒前
量子星尘发布了新的文献求助10
13秒前
Vresty完成签到,获得积分10
15秒前
糯米团的完成签到 ,获得积分10
17秒前
17秒前
Yunsong发布了新的文献求助10
17秒前
黑猫完成签到,获得积分20
18秒前
热心市民小红花应助千余采纳,获得10
19秒前
19秒前
20秒前
lan完成签到,获得积分10
20秒前
火星上念梦发布了新的文献求助150
20秒前
Enckson完成签到,获得积分10
21秒前
火星上的羽毛完成签到,获得积分10
22秒前
留留完成签到,获得积分10
23秒前
lan发布了新的文献求助10
23秒前
我爱金哥发布了新的文献求助10
23秒前
24秒前
小叶曲完成签到,获得积分10
24秒前
27秒前
高分求助中
A new approach to the extrapolation of accelerated life test data 1000
ACSM’s Guidelines for Exercise Testing and Prescription, 12th edition 500
‘Unruly’ Children: Historical Fieldnotes and Learning Morality in a Taiwan Village (New Departures in Anthropology) 400
Indomethacinのヒトにおける経皮吸収 400
Phylogenetic study of the order Polydesmida (Myriapoda: Diplopoda) 370
基于可调谐半导体激光吸收光谱技术泄漏气体检测系统的研究 350
Robot-supported joining of reinforcement textiles with one-sided sewing heads 320
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3988868
求助须知:如何正确求助?哪些是违规求助? 3531255
关于积分的说明 11253071
捐赠科研通 3269858
什么是DOI,文献DOI怎么找? 1804822
邀请新用户注册赠送积分活动 881994
科研通“疑难数据库(出版商)”最低求助积分说明 809035