Discovery and development of small molecule allosteric modulators of glycoprotein hormone receptors
被引:49
作者:
Nataraja, Selvaraj G.
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h-index: 0
机构:
TocopheRx Inc, 15 New England Execut Pk,Suite 1087, Burlington, MA 01803 USATocopheRx Inc, 15 New England Execut Pk,Suite 1087, Burlington, MA 01803 USA
Nataraja, Selvaraj G.
[1
]
Yu, Henry N.
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h-index: 0
机构:
TocopheRx Inc, 15 New England Execut Pk,Suite 1087, Burlington, MA 01803 USA
EMD Serono Res & Dev Inst Inc, Billerica, MA USATocopheRx Inc, 15 New England Execut Pk,Suite 1087, Burlington, MA 01803 USA
Yu, Henry N.
[1
,2
]
Palmer, Stephen S.
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机构:
TocopheRx Inc, 15 New England Execut Pk,Suite 1087, Burlington, MA 01803 USATocopheRx Inc, 15 New England Execut Pk,Suite 1087, Burlington, MA 01803 USA
Palmer, Stephen S.
[1
]
机构:
[1] TocopheRx Inc, 15 New England Execut Pk,Suite 1087, Burlington, MA 01803 USA
[2] EMD Serono Res & Dev Inst Inc, Billerica, MA USA
small molecule allosteric modulators;
follicle-stimulating hormone;
leutinizing hormone/chorionic gonadotropin;
thyroid-stimulating hormone;
G protein-coupled receptor;
glycoprotein hormone receptors;
leucine-rich repeat;
FOLLICLE-STIMULATING-HORMONE;
PROTEIN-COUPLED RECEPTORS;
HUMAN CHORIONIC-GONADOTROPIN;
OVARIAN HYPERSTIMULATION SYNDROME;
HUMAN LUTEINIZING-HORMONE;
THYROTROPIN-RELEASING-HORMONE;
HUMAN CHORIOGONADOTROPIN-BETA;
N-LINKED OLIGOSACCHARIDES;
LEUCINE-RICH REPEATS;
FSH RECEPTOR;
D O I:
10.3389/fendo.2015.00142
中图分类号:
R5 [内科学];
学科分类号:
1002 ;
100201 ;
摘要:
Glycoprotein hormones, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and thyroid-stimulating hormone (TSH) are heterodimeric proteins with a common alpha-subunit and hormone-specific beta-subunit. These hormones are dominant regulators of reproduction and metabolic processes. Receptors for the glycoprotein hormones belong to the family of G protein-coupled receptors. FSH receptor (FSHR) and LH receptor are primarily expressed in somatic cells in ovary and testis to promote egg and sperm production in women and men, respectively. TSH receptor is expressed in thyroid cells and regulates the secretion of T3 and T4. Glycoprotein hormones bind to the large extracellular domain of the receptor and cause a conformational change in the receptor that leads to activation of more than one intracellular signaling pathway. Several small molecules have been described to activate/inhibit glycoprotein hormone receptors through allosteric sites of the receptor. Small molecule allosteric modulators have the potential to be administered orally to patients, thus improving the convenience of treatment. It has been a challenge to develop a small molecule allosteric agonist for glycoprotein hormones that can mimic the agonistic effects of the large natural ligand to activate similar signaling pathways. However, in the past few years, there have been several promising reports describing distinct chemical series with improved potency in preclinical models. In parallel, proposal of new structural model for FSHR and in silico docking studies of small molecule ligands to glycoprotein hormone receptors provide a giant leap on the understanding of the mechanism of action of the natural ligands and new chemical entities on the receptors. This review will focus on the current status of small molecule allosteric modulators of glycoprotein hormone receptors, their effects on common signaling pathways in cells, their utility for clinical application as demonstrated in preclinical models, and use of these molecules as novel tools to dissect the molecular signaling pathways of these receptors.
机构:
Univ Calif San Francisco, UCSF Womens Hlth Clin Res Ctr, San Francisco, CA 94143 USA
Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, UCSF Ctr Reprod Hlth, San Francisco, CA 94143 USAUniv Calif San Francisco, UCSF Womens Hlth Clin Res Ctr, San Francisco, CA 94143 USA
Kashyap, Sonya
;
Parker, Kasey
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h-index: 0
机构:
Ottawa Hlth Res Inst, Ottawa, ON, CanadaUniv Calif San Francisco, UCSF Womens Hlth Clin Res Ctr, San Francisco, CA 94143 USA
Parker, Kasey
;
Cedars, Marcelle I.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Calif San Francisco, UCSF Womens Hlth Clin Res Ctr, San Francisco, CA 94143 USA
Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, UCSF Ctr Reprod Hlth, San Francisco, CA 94143 USAUniv Calif San Francisco, UCSF Womens Hlth Clin Res Ctr, San Francisco, CA 94143 USA
Cedars, Marcelle I.
;
Rosenwaks, Zev
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h-index: 0
机构:
Weill Cornell Med Coll, Ronald O Perelman & Claudia Cohen Ctr Reprod Med, New York, NY USAUniv Calif San Francisco, UCSF Womens Hlth Clin Res Ctr, San Francisco, CA 94143 USA
机构:
GlaxoSmithKline Res & Dev Ltd, Dept Biol Reagents & Assay Dev, Res Triangle Pk, NC 27709 USAGlaxoSmithKline Res & Dev Ltd, Dept Biol Reagents & Assay Dev, Res Triangle Pk, NC 27709 USA
机构:
Walter & Eliza Hall Inst Med Res, Struct Biol Div, Parkville, Vic 3052, Australia
Univ Melbourne, Dept Med Biol, Parkville, Vic 3052, AustraliaWalter & Eliza Hall Inst Med Res, Struct Biol Div, Parkville, Vic 3052, Australia
Kumar, Kaavya Krishna
;
Burgess, Antony W.
论文数: 0引用数: 0
h-index: 0
机构:
Walter & Eliza Hall Inst Med Res, Struct Biol Div, Parkville, Vic 3052, Australia
Univ Melbourne, Dept Surg, Parkville, Vic 3052, AustraliaWalter & Eliza Hall Inst Med Res, Struct Biol Div, Parkville, Vic 3052, Australia
Burgess, Antony W.
;
Gulbis, Jacqueline M.
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h-index: 0
机构:
Walter & Eliza Hall Inst Med Res, Struct Biol Div, Parkville, Vic 3052, Australia
Univ Melbourne, Dept Med Biol, Parkville, Vic 3052, AustraliaWalter & Eliza Hall Inst Med Res, Struct Biol Div, Parkville, Vic 3052, Australia
机构:
Univ Calif San Francisco, UCSF Womens Hlth Clin Res Ctr, San Francisco, CA 94143 USA
Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, UCSF Ctr Reprod Hlth, San Francisco, CA 94143 USAUniv Calif San Francisco, UCSF Womens Hlth Clin Res Ctr, San Francisco, CA 94143 USA
Kashyap, Sonya
;
Parker, Kasey
论文数: 0引用数: 0
h-index: 0
机构:
Ottawa Hlth Res Inst, Ottawa, ON, CanadaUniv Calif San Francisco, UCSF Womens Hlth Clin Res Ctr, San Francisco, CA 94143 USA
Parker, Kasey
;
Cedars, Marcelle I.
论文数: 0引用数: 0
h-index: 0
机构:
Univ Calif San Francisco, UCSF Womens Hlth Clin Res Ctr, San Francisco, CA 94143 USA
Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, UCSF Ctr Reprod Hlth, San Francisco, CA 94143 USAUniv Calif San Francisco, UCSF Womens Hlth Clin Res Ctr, San Francisco, CA 94143 USA
Cedars, Marcelle I.
;
Rosenwaks, Zev
论文数: 0引用数: 0
h-index: 0
机构:
Weill Cornell Med Coll, Ronald O Perelman & Claudia Cohen Ctr Reprod Med, New York, NY USAUniv Calif San Francisco, UCSF Womens Hlth Clin Res Ctr, San Francisco, CA 94143 USA
机构:
GlaxoSmithKline Res & Dev Ltd, Dept Biol Reagents & Assay Dev, Res Triangle Pk, NC 27709 USAGlaxoSmithKline Res & Dev Ltd, Dept Biol Reagents & Assay Dev, Res Triangle Pk, NC 27709 USA
机构:
Walter & Eliza Hall Inst Med Res, Struct Biol Div, Parkville, Vic 3052, Australia
Univ Melbourne, Dept Med Biol, Parkville, Vic 3052, AustraliaWalter & Eliza Hall Inst Med Res, Struct Biol Div, Parkville, Vic 3052, Australia
Kumar, Kaavya Krishna
;
Burgess, Antony W.
论文数: 0引用数: 0
h-index: 0
机构:
Walter & Eliza Hall Inst Med Res, Struct Biol Div, Parkville, Vic 3052, Australia
Univ Melbourne, Dept Surg, Parkville, Vic 3052, AustraliaWalter & Eliza Hall Inst Med Res, Struct Biol Div, Parkville, Vic 3052, Australia
Burgess, Antony W.
;
Gulbis, Jacqueline M.
论文数: 0引用数: 0
h-index: 0
机构:
Walter & Eliza Hall Inst Med Res, Struct Biol Div, Parkville, Vic 3052, Australia
Univ Melbourne, Dept Med Biol, Parkville, Vic 3052, AustraliaWalter & Eliza Hall Inst Med Res, Struct Biol Div, Parkville, Vic 3052, Australia