Small-molecule agonists for the thyrotropin receptor stimulate thyroid function in human thyrocytes and mice.
Seven-transmembrane-spanning receptors (7TMRs) are prominent drug targets. However, small-molecule ligands for 7-transmembrane-spanning receptors for which the natural ligands are large, heterodimeric glycoprotein hormones, like thyroid-stimulating hormone (TSH; thyrotropin), have only recently been reported, and none are approved for human use. We have used quantitative high-throughput screening to identify a small-molecule TSH receptor (TSHR) agonist that was modified to produce a second agonist with increased potency. We show that these agonists are highly selective for human TSHR versus other glycoprotein hormone receptors and interact with the receptor's serpentine domain. A binding pocket within the transmembrane domain was defined by docking into a TSHR homology model and was supported by site-directed mutagenesis. In primary cultures of human thyrocytes, both TSH and the agonists increase mRNA levels for thyroglobulin, thyroperoxidase, sodium iodide symporter, and deiodinase type 2, and deiodinase type 2 enzyme activity. Moreover, oral administration of the agonist stimulated thyroid function in mice, resulting in increased serum thyroxine and thyroidal radioiodide uptake. Thus, we discovered a small molecule that activates human TSHR in vitro, is orally active in mice, and could be a lead for development of drugs to use in place of recombinant human TSH in patients with thyroid cancer.
Neumann
Susanne
S
Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Huang
Wenwei
W
Titus
Steve
S
Krause
Gerd
G
Kleinau
Gunnar
G
Alberobello
Anna Teresa
AT
Zheng
Wei
W
Southall
Noel T
NT
Inglese
James
J
Austin
Christopher P
CP
Celi
Francesco S
FS
Gavrilova
Oksana
O
Thomas
Craig J
CJ
Raaka
Bruce M
BM
Gershengorn
Marvin C
MC
D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D015394:Molecular Structure; D009930:Organic Chemicals / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D052999:Quinazolinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011989:Receptors, Thyrotropin / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013954:Thyroglobulin / Q000235:genetics / Q000378:metabolism; D013961:Thyroid Gland / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D013972:Thyrotropin / Q000494:pharmacology; D014162:Transfection
C543829:3-(furan-2-ylmethyl)-2-(4-methoxy-3-(phenoxymethyl)phenyl)-2,3-dihydroquinazolin-4(1H)-one; D000081:Acetamides; C543827:N-(4-(5-(3-(furan-2-ylmethyl)-4-oxo-1,2,3,4-tetrahydroquinazolin-2-yl)-2-methoxybenzyloxy)phenyl)acetamide; C543828:N-(4-(5-(3-benzyl-5-hydroxy-4-oxo-1,2,3,4-tetrahydroquinazolin-2-yl)-2-methoxybenzyloxy)phenyl)acetamide; D009930:Organic Chemicals; D052999:Quinazolinones; D011989:Receptors, Thyrotropin; D013972:Thyrotropin; D013954:Thyroglobulin; D000242:Cyclic AMP; D007453:Iodide Peroxidase