Repurposing Approved Drugs as Inhibitors of K
Animals
Bayes Theorem
CHO Cells
Cricetulus
Dihydropyridines
/ chemistry
Drug Repositioning
/ methods
Facies
HEK293 Cells
Humans
Hyperventilation
/ drug therapy
Intellectual Disability
/ drug therapy
KCNQ1 Potassium Channel
/ antagonists & inhibitors
Machine Learning
NAV1.8 Voltage-Gated Sodium Channel
/ metabolism
Potassium Channel Blockers
/ chemistry
Small Molecule Libraries
/ chemistry
Sodium Channel Blockers
/ chemistry
Structure-Activity Relationship
Voltage-Gated Sodium Channel Blockers
/ chemistry
Kv7.1
Nav1.8
Pitt Hopkins syndrome
high throughput screen
repurposing
Journal
Pharmaceutical research
ISSN: 1573-904X
Titre abrégé: Pharm Res
Pays: United States
ID NLM: 8406521
Informations de publication
Date de publication:
22 Jul 2019
22 Jul 2019
Historique:
received:
16
10
2018
accepted:
10
07
2019
entrez:
24
7
2019
pubmed:
25
7
2019
medline:
21
8
2019
Statut:
epublish
Résumé
Pitt Hopkins Syndrome (PTHS) is a rare genetic disorder caused by mutations of a specific gene, transcription factor 4 (TCF4), located on chromosome 18. PTHS results in individuals that have moderate to severe intellectual disability, with most exhibiting psychomotor delay. PTHS also exhibits features of autistic spectrum disorders, which are characterized by the impaired ability to communicate and socialize. PTHS is comorbid with a higher prevalence of epileptic seizures which can be present from birth or which commonly develop in childhood. Attenuated or absent TCF4 expression results in increased translation of peripheral ion channels K We now describe a high throughput screen (HTS) of 1280 approved drugs and machine learning models developed from this data. The ion channels were expressed in either CHO (K The HTS delivered 55 inhibitors of K This work could lead to the potential repurposing of nicardipine or other dihydropyridine calcium channel antagonists as potential treatments for PTHS acting via Na
Identifiants
pubmed: 31332533
doi: 10.1007/s11095-019-2671-y
pii: 10.1007/s11095-019-2671-y
pmc: PMC6814258
mid: NIHMS1054651
doi:
Substances chimiques
Dihydropyridines
0
KCNQ1 Potassium Channel
0
NAV1.8 Voltage-Gated Sodium Channel
0
Potassium Channel Blockers
0
Small Molecule Libraries
0
Sodium Channel Blockers
0
Voltage-Gated Sodium Channel Blockers
0
Types de publication
Journal Article
Langues
eng
Pagination
137Subventions
Organisme : NIGMS NIH HHS
ID : R43 GM122196
Pays : United States
Organisme : Pitt Hopkins Research Foundation
ID : N/A
Organisme : National Institute of General Medical Sciences
ID : R44GM122196-02A1
Organisme : NIGMS NIH HHS
ID : R44 GM122196
Pays : United States
Organisme : National Institute of General Medical Sciences
ID : R43GM122196
Références
Mol Pharm. 2018 Oct 1;15(10):4361-4370
pubmed: 30114914
Mol Pharmacol. 2018 Sep;94(3):1057-1068
pubmed: 29884691
Genomics. 1999 Apr 15;57(2):323-31
pubmed: 10198179
Hum Mol Genet. 2007 Jun 15;16(12):1488-94
pubmed: 17478476
ACS Omega. 2019 Jan 31;4(1):2353-2361
pubmed: 30729228
Sci Transl Med. 2009 Oct 14;1(2):2ra6
pubmed: 20368164
J Pharmacol Exp Ther. 2012 Jun;341(3):743-55
pubmed: 22419765
Neuron. 2016 Apr 6;90(1):43-55
pubmed: 26971948
Neurosci Lett. 2010 Dec 10;486(2):78-83
pubmed: 20816723
Chem Res Toxicol. 2010 Mar 15;23(3):664-76
pubmed: 20151638
Pharm Res. 2018 Dec 17;36(2):27
pubmed: 30560386
Am J Physiol Gastrointest Liver Physiol. 2007 Dec;293(6):G1288-99
pubmed: 17916649
Channels (Austin). 2015;9(6):360-6
pubmed: 26646477
Med Pregl. 2000 Jan-Feb;53(1-2):51-4
pubmed: 10953551
Biochem Soc Trans. 2007 Nov;35(Pt 5):1074-6
pubmed: 17956282
Eur J Pharmacol. 2011 Jun 1;659(2-3):124-9
pubmed: 21497592
Metallomics. 2019 Mar 20;11(3):696-706
pubmed: 30839007
Drug Discov Today. 2011 Apr;16(7-8):298-310
pubmed: 21376136
Nat Neurosci. 1999 Jun;2(6):541-8
pubmed: 10448219
Mol Pharm. 2019 Apr 1;16(4):1620-1632
pubmed: 30779585
Am J Hum Genet. 2007 May;80(5):994-1001
pubmed: 17436255
J Chem Inf Model. 2015 Jun 22;55(6):1231-45
pubmed: 25994950
ChemMedChem. 2012 Oct;7(10):1712-40
pubmed: 22945552
Pain. 2007 Oct;131(3):243-57
pubmed: 17766042
J Cheminform. 2014 Aug 04;6:38
pubmed: 25302078
Pharmacol Rev. 2005 Dec;57(4):411-25
pubmed: 16382099
Aust Paediatr J. 1978 Sep;14(3):182-4
pubmed: 728011
Drug Metab Dispos. 2011 Feb;39(2):337-44
pubmed: 21068194
PLoS Negl Trop Dis. 2015 Jun 26;9(6):e0003878
pubmed: 26114876
Mol Pharm. 2013 Mar 4;10(3):1008-19
pubmed: 23339484
FASEB J. 2011 Dec;25(12):4264-73
pubmed: 21859894
Mol Pharm. 2009 Sep-Oct;6(5):1591-603
pubmed: 19673539
Mol Pharm. 2019 Feb 4;16(2):898-906
pubmed: 30589555
Drug Metab Dispos. 2010 Dec;38(12):2302-8
pubmed: 20843939
PLoS Comput Biol. 2009 Dec;5(12):e1000594
pubmed: 20011107
J Pharmacol Toxicol Methods. 2014 Mar-Apr;69(2):115-40
pubmed: 24361690
J Physiol. 2008 Apr 1;586(7):1785-9
pubmed: 18174212
Nature. 1996 Jan 18;379(6562):257-62
pubmed: 8538791
Pain. 1998 Nov;78(2):107-14
pubmed: 9839820
F1000Res. 2015 Oct 20;4:1091
pubmed: 26834994
Mol Pharm. 2018 Oct 1;15(10):4346-4360
pubmed: 29672063
J Chem Inf Model. 2015 Jun 22;55(6):1246-60
pubmed: 25995041
Am J Hum Genet. 2007 May;80(5):988-93
pubmed: 17436254
PLoS One. 2014 Mar 12;9(3):e91167
pubmed: 24621589
Mol Pharm. 2010 Dec 6;7(6):2120-31
pubmed: 20831193