A low-molecular-weight antagonist for the human thyrotropin receptor with therapeutic potential for hyperthyroidism.
Low-molecular-weight (LMW) antagonists for TSH receptor (TSHR) may have therapeutic potential as orally active drugs to block stimulating antibodies (TsAbs) in Graves' hyperthyroidism. We describe an approach to identify LMW ligands for TSHR based on Org41841, a LMW partial agonist for the LH/choriogonadotropin receptor and TSHR. We used molecular modeling and functional experiments to guide the chemical modification of Org41841. We identified an antagonist (NIDDK/CEB-52) that selectively inhibits activation of TSHR by both TSH and TsAbs. Whereas initially characterized in cultured cells overexpressing TSHRs, the antagonist was also active under more physiologically relevant conditions in primary cultures of human thyrocytes expressing endogenous TSHRs in which it inhibited TSH- and TsAb-induced up-regulation of mRNA transcripts for thyroperoxidase. Our results establish this LMW compound as a lead for the development of higher potency antagonists and serve as proof of principle that LMW ligands that target TSHR could serve as drugs in patients with Graves' disease.
Neumann
Susanne
S
National Institute of Diabetes and Digestive and Kidney Diseases, Clinical Endocrinology Branch, National Institutes of Health, 50 South Drive, Bethesda, Maryland 20892-8029, USA.
Kleinau
Gunnar
G
Costanzi
Stefano
S
Moore
Susanna
S
Jiang
Jian-kang
JK
Raaka
Bruce M
BM
Thomas
Craig J
CJ
Krause
Gerd
G
Gershengorn
Marvin C
MC
D013956:Antithyroid Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D003198:Computer Simulation; D006801:Humans; D006980:Hyperthyroidism / Q000188:drug therapy* / Q000378:metabolism; D015394:Molecular Structure; D008970:Molecular Weight; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding / Q000235:genetics; D011989:Receptors, Thyrotropin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D013956:Antithyroid Agents; D011989:Receptors, Thyrotropin