A screen of repurposed drugs identifies AMHR2/MISR2 agonists as potential contraceptives.
Animals
Anthracenes
/ chemistry
Contraceptive Agents
/ chemistry
Drug Evaluation, Preclinical
Drug Repositioning
Female
Humans
Mice
Nitriles
/ chemistry
Ovarian Follicle
/ drug effects
Pyrazoles
/ chemistry
Pyrimidines
/ chemistry
Rats
Receptors, Peptide
/ agonists
Receptors, Transforming Growth Factor beta
/ agonists
Small Molecule Libraries
/ chemistry
Thiazoles
/ chemistry
AMH
AMHR2 agonists
contraception
folliculogenesis
small molecules screen
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
12 04 2022
12 04 2022
Historique:
entrez:
5
4
2022
pubmed:
6
4
2022
medline:
19
4
2022
Statut:
ppublish
Résumé
We identified the anti-Mullerian hormone (also known as Müllerian inhibiting substance or MIS) as an inhibitory hormone that induces long-term contraception in mammals. The type II receptor to this hormone, AMHR2 (also known as MISR2), represents a promising druggable target for the modulation of female reproduction with a mechanism of action distinct from steroidal contraceptives. We designed an in vitro platform to screen and validate small molecules that can activate MISR2 signaling and suppress ovarian folliculogenesis. Using a bone morphogenesis protein (BMP)–response element luciferase reporter cell–based assay, we screened 5,440 compounds from a repurposed drug library. Positive hits in this screen were tested for specificity and potency in luciferase dose–response assays, and biological activity was tested in ex vivo Mullerian duct regression bioassays. Selected candidates were further evaluated in ex vivo follicle/ovary culture assays and in vivo in mice and rats. Here, we report that SP600125, CYC-116, gandotinib, and ruxolitinib can specifically inhibit primordial follicle activation and repress folliculogenesis by stimulating the MISR2 pathway.
Identifiants
pubmed: 35380904
doi: 10.1073/pnas.2122512119
pmc: PMC9169708
doi:
Substances chimiques
4-methyl-5-(2-(4-morpholinophenylamino)pyrimidin-4-yl)thiazol-2-amine
0
Anthracenes
0
Contraceptive Agents
0
Nitriles
0
Pyrazoles
0
Pyrimidines
0
Receptors, Peptide
0
Receptors, Transforming Growth Factor beta
0
Small Molecule Libraries
0
Thiazoles
0
anti-Mullerian hormone receptor
0
pyrazolanthrone
1TW30Y2766
ruxolitinib
82S8X8XX8H
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e2122512119Références
Proc Natl Acad Sci U S A. 2021 May 18;118(20):
pubmed: 33980714
N Engl J Med. 2020 May 7;382(19):1800-1810
pubmed: 32320566
Nat Commun. 2016 Jan 12;7:10055
pubmed: 26753790
N Engl J Med. 2015 Jan 29;372(5):426-35
pubmed: 25629741
Nat Genet. 2002 Nov;32(3):408-10
pubmed: 12368913
ACS Chem Biol. 2010 Feb 19;5(2):245-53
pubmed: 20020776
Curr Cancer Drug Targets. 2015;15(5):375-93
pubmed: 25895501
J Reprod Fertil. 1968 Dec;17(3):555-7
pubmed: 5715685
Blood Cancer J. 2013 Apr 12;3:e109
pubmed: 23584399
Signal Transduct Target Ther. 2021 May 31;6(1):201
pubmed: 34054126
Hum Reprod Update. 2006 Sep-Oct;12(5):557-71
pubmed: 16672246
Horm Res Paediatr. 2020;93(11-12):599-608
pubmed: 33887724
J Endocr Soc. 2019 Jul 22;3(11):2123-2134
pubmed: 31687639
Sci Rep. 2021 Jan 13;11(1):1079
pubmed: 33441767
J Surg Res. 1977 Aug;23(2):141-8
pubmed: 886843
Curr Opin Endocrinol Diabetes Obes. 2018 Dec;25(6):399-405
pubmed: 30320617
Toxicol Sci. 1998 Nov;46(1):61-74
pubmed: 9928669
Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9348-53
pubmed: 12878721
Endocrinology. 2008 Jan;149(1):108-15
pubmed: 17947357
Trends Endocrinol Metab. 2003 Mar;14(2):91-7
pubmed: 12591180
N Engl J Med. 2012 Mar 1;366(9):799-807
pubmed: 22375971
Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13681-6
pubmed: 11717429
F1000Res. 2018 Jan 17;7:82
pubmed: 29399328
Proc Natl Acad Sci U S A. 2021 Jun 29;118(26):
pubmed: 34155118
Leuk Res. 2018 Aug;71:82-88
pubmed: 30025280
Endocrinology. 2002 Mar;143(3):1076-84
pubmed: 11861535
J Clin Endocrinol Metab. 1987 Dec;65(6):1231-7
pubmed: 3119654
Sci Rep. 2016 Mar 31;6:23790
pubmed: 27030385
Nat Med. 2017 Apr 7;23(4):405-408
pubmed: 28388612
Biomol Ther (Seoul). 2019 May 1;27(3):311-317
pubmed: 30332888
Hum Reprod. 1996 Jul;11(7):1484-6
pubmed: 8671489
FEBS Lett. 2013 Jun 19;587(12):1749-53
pubmed: 23624077
Proc Natl Acad Sci U S A. 2017 Feb 28;114(9):E1688-E1697
pubmed: 28137855
J Exp Clin Assist Reprod. 2006 Mar 01;3:2
pubmed: 16509981
J Biol Chem. 2002 Feb 15;277(7):4883-91
pubmed: 11729207
Technology. 2013 Sep;1(1):63-71
pubmed: 24729676
Neurobiol Dis. 2016 Aug;92(Pt B):137-43
pubmed: 26851503
Ther Adv Hematol. 2012 Dec;3(6):341-54
pubmed: 23606937
J Allergy Clin Immunol. 2020 Feb;145(2):572-582
pubmed: 31629805
Elife. 2019 Jun 24;8:
pubmed: 31232694
Mol Hum Reprod. 2018 Nov 1;24(11):533-542
pubmed: 30247637