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• W4362602466 abstract "Background: Treatment of Graves’ hyperthyroidism (GH) and Graves’ orbitopathy (GO) is far from adequate, hence new substances, which 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, which 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 read-outs. 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. A 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), 1,000 (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 read-out. SYD5115 induced 100% inhibition of the M22-induced cAMP levels with a potency of 193 nM. Compared to 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." @default.
• W4362602466 created "2023-04-06" @default.
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• W4362602466 date "2023-05-08" @default.
• W4362602466 modified "2023-09-28" @default.
• W4362602466 title "THYROTROPIN RECEPTOR ANTAGONISM BY A NOVEL SMALL MOLECULE: PRE-CLINICAL IN VITRO OBSERVATIONS" @default.
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• W4362602466 doi "https://doi.org/10.1089/thy.2022.0694" @default.
• W4362602466 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/37016815" @default.
• W4362602466 hasPublicationYear "2023" @default.
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