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BioAssay: AID 488964

Summary of probe development for inhibitors of the two-pore domain potassium channel KCNK9

Name: Primary cell-based screen for identification of compounds that inhibit the two-pore domain potassium channel KCNK9 ..more
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AID: 488964
Data Source: Johns Hopkins Ion Channel Center (JHICC_KCNK9_Inh_Summary)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
BioAssay Version:
Deposit Date: 2010-10-28
Modify Date: 2013-03-27
Target
Sequence: potassium channel subfamily K member 9 [Homo sapiens]
Description ..   

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AIDNameTypeComment
488922Primary cell-based screen for identification of compounds that inhibit the two-pore domain potassium channel KCNK9Screeningdepositor-specified cross reference
492992Confirmatory screen for identification of compounds that inhibit the two-pore domain potassium channel (KCNK9)Screeningdepositor-specified cross reference
492993Specificity screen against Kir2.1 for compounds that modulate the two-pore domain potassium channel (KCNK9)Screeningdepositor-specified cross reference
492997Second counter screen for compounds that modulate the two-pore domain potassium channel (KCNK9)Screeningdepositor-specified cross reference
504846SAR analysis for compounds that inhibit the two-pore domain potassium channel KCNK9Confirmatorydepositor-specified cross reference: SAR analysis for compounds that inhibit the two-pore domain potassium channel KCNK9
504902SAR Analysis for the identification of selective inhibitors of KCNK9 against parental cells: FluxOR Assay CRCConfirmatorydepositor-specified cross reference
504920SAR Analysis for the identification of selective inhibitors of the two-pore domain potassium channel KCNK9 in hERG expressing cells: FluxOR Assay CRC for hERG SpecificityConfirmatorydepositor-specified cross reference
504922SAR Analysis for the identification of selective inhibitors of the two-pore domain potassium channel KCNK9 in Kir2.1 expressing cells: FluxOR Assay CRCConfirmatorydepositor-specified cross reference
540321SAR Analysis for the identification of selective inhibitors of the two-pore domain potassium channel KCNK9 in Kir2.1 expressing cells: FluxOR Assay CRC 2Confirmatorydepositor-specified cross reference
540322SAR analysis for compounds that inhibit the two-pore domain potassium channel KCNK9 IIConfirmatorydepositor-specified cross reference
540323SAR Analysis for the identification of selective inhibitors of the two-pore domain potassium channel KCNK9 in hERG expressing cells: FluxOR Assay CRC 2Confirmatorydepositor-specified cross reference
540324SAR Analysis for the identification of selective inhibitors of KCNK9 against parental cells: FluxOR Assay CRC 2Confirmatorydepositor-specified cross reference
588724SAR analysis for compounds that inhibit the two-pore domain potassium channel KCNK9 IIIConfirmatorydepositor-specified cross reference
588741SAR Analysis for the identification of selective inhibitors of the two-pore domain potassium channel KCNK9 in hERG expressing cells: FluxOR Assay CRC 3Confirmatorydepositor-specified cross reference
588759SAR Analysis for the identification of selective inhibitors of KCNK9 against parental cells: FluxOR Assay CRC 3Confirmatorydepositor-specified cross reference
588760SAR Analysis for the identification of selective inhibitors of the two-pore domain potassium channel KCNK9 in Kir2.1 expressing cells: FluxOR Assay CRC 3Confirmatorydepositor-specified cross reference
588761SAR Analysis for the identification of selective inhibitors of the two-pore domain potassium channel KCNK9 in KCNQ2 expressing cells: FluxOR Assay CRCConfirmatorydepositor-specified cross reference
588776SAR Analysis for the identification of selective inhibitors of the two-pore domain potassium channel KCNK9 in KCNK3 expressing cells: FluxOR Assay CRC 1Confirmatorydepositor-specified cross reference
588798SAR Analysis for the identification of selective inhibitors of the two-pore domain potassium channel KCNK9 in KCNQ2 expressing cells: FluxOR Assay CRC 3Confirmatorydepositor-specified cross reference
588800SAR Analysis for the identification of selective inhibitors of the two-pore domain potassium channel KCNK9 in KCNQ2 expressing cells: FluxOR Assay CRC 2Confirmatorydepositor-specified cross reference
623881SAR Analysis for the identification of selective inhibitors of the two-pore domain potassium channel KCNK9 in Kir2.1 expressing cells: FluxOR Assay CRC 4Confirmatorydepositor-specified cross reference
623883SAR Analysis for the identification of inhibitors of the two-pore domain potassium channel KCNK9 - Selectivity assay against hERG: FluxOR Assay CRC 4Confirmatorydepositor-specified cross reference
623884SAR Analysis for the identification of selective inhibitors of KCNK9 against parental cells: FluxOR Assay CRC 4Confirmatorydepositor-specified cross reference
623886SAR Analysis for the identification of inhibitors of the two-pore domain potassium channel KCNK9 - Selectivity assay against KCNQ2: FluxOR Assay CRCConfirmatorydepositor-specified cross reference
623887SAR analysis for compounds that inhibit the two-pore domain potassium channel KCNK9 4Confirmatorydepositor-specified cross reference
623894SAR Analysis for the identification of inhibitors of the two-pore domain potassium channel KCNK9 - Selectivity assay against KCNK3: FluxOR Assay CRC 3Confirmatorydepositor-specified cross reference
623898SAR analysis for the identification of selective inhibitors of the two-pore domain potassium channel (KCNK9): Automated ElectrophysiologyConfirmatorydepositor-specified cross reference
623912SAR Analysis for the identification of inhibitors of the two-pore domain potassium channel KCNK9 - Selectivity assay against KCNK3: FluxOR Assay CRC 2Confirmatorydepositor-specified cross reference
623913SAR Analysis for the identification of inhibitors of the two-pore domain potassium channel KCNK9 - Selectivity assay against KCNQ2: FluxOR Assay CRC 4Confirmatorydepositor-specified cross reference
623914SAR Analysis for the identification of inhibitors of the two-pore domain potassium channel KCNK9 - Selectivity assay against KCNQ2: FluxOR Assay CRC 2Confirmatorydepositor-specified cross reference
623915SAR analysis for the identification of selective inhibitors of the two-pore domain potassium channel (KCNK9) -selectivity assay against KCNK3: Automated ElectrophysiologyConfirmatorydepositor-specified cross reference
624121SAR analysis for the identification of selective inhibitors of the two-pore domain potassium channel (KCNK9): Manual ElectrophysiologyOtherdepositor-specified cross reference
Description:
Name: Primary cell-based screen for identification of compounds that inhibit the two-pore domain potassium channel KCNK9
Data Source: Johns Hopkins Ion Channel Center (JHICC_KCNK9_Inh_Summary)
BioAssay Type: Summary
Depositor Category: NIH Molecular Libraries Probe Production Network

Source (MLPCN Center Name): Johns Hopkins Ion Channel Center (JHICC)
Center Affiliation: Johns Hopkins University, School of Medicine
Screening Center PI: Min Li, Ph.D.
Assay Provider: Meng Wu, Ph.D. , Johns Hopkins University, School of Medicine
Network: Molecular Libraries Probe Production Centers Network (MLPCN)
Grant Proposal Number: 1 R03 MH090849-01
Grant Proposal PI: Meng Wu, Ph.D. , Johns Hopkins University, School of Medicine
Assay Implementation: Melissa Miller, Joseph Babcock, Amy Scott M.S., Shunyou Long M.S., David Meyers Ph.D., Owen McManus Ph.D., and Meng Wu Ph.D.


Description:

KCNK9 (also termed K2p9.1 or TASK-3) is a member of the two-pore domain family (KCNK) of potassium channels that contribute to resting membrane potential and the regulation of cell excitability by generating background currents [1-2].

In addition to its role in neurons where KCNK9 is most abundantly expressed, recent studies show that KCNK9 plays critical roles in a wide variety of human pathophysiologies. For example, KCNK9 is overexpressed in various human cancers and its exogenous overexpression promotes cell proliferation in culture and tumor development in animal models [3-4]. Moreover, KCNK9 deficiency causes a primary hyperaldosteronism in mouse [5]. A more recent study reports that KCNK9 mutation causes Birk Barel mental retardation dysmorphism syndrome in humans [6]. These findings suggest that KCNK9 may be a potential new therapeutic target for treating human diseases [7]. However, there are no suitable chemical probes to investigate the physiological roles of KCNK9 channels.

The objective of the current screen is to identify compounds that inhibit the flow of ions through KCNK9 using a HEK293 cell line that stably expresses this channel. Compounds selected as KCNK9 inhibitors will later be counter-screened for specificity.

Keywords:

KCNK9, TASK3, Two-pore domain potassium channel 9, HTS assay, 384, primary, inhibitor, blocker, FDSS, Thallium, fluorescence, Kinetic, FluxOR, JHICC, Johns Hopkins, Molecular Libraries Probe Production Centers Network, MLPCN.


References:
1. Chapman, CG, et al., Cloning, localisation and functional expression of a novel human, cerebellum specific, two pore domain potassium channel. Brain Res Mol Brain Res, 2000. 82(1-2):p. 74-83. PMID: 11042359
2. Goldstein, S. A. N., D. A. Bayliss, et al. (2005). International Union of Pharmacology. LV. Nomenclature and Molecular Relationships of Two-P Potassium Channels. Pharmacol Rev 57(4): 527-540.PMID: 16382106
3. Mu, D., et al., Genomic amplification and oncogenic properties of the KCNK9 potassium channel gene. Cancer Cell, 2003. 3(3): p. 297-302. PMID: 12676587
4. Pei, L., et al., Oncogenic potential of TASK3 (Kcnk9) depends on K+ channel function. Proc Natl Acad Sci U S A, 2003. 100(13): p. 7803-7. PMID: 12782791
5. Davies LA , et al., TASK channel deletion in mice causes primary hyperaldosteronism. Proc Natl Acad Sci U S A. 2008. 105(6):p. 2203-8. PMID: 18250325
6. Barel O , et al., Maternally inherited Birk Barel mental retardation dysmorphism syndrome caused by a mutation in the genomically imprinted potassium channel KCNK9. Am J Hum Genet. 2008. 83(2):p. 193-9.PMID: 18678320
7. Bayliss, D. A. and P. Q. Barrett (2008). Emerging roles for two-pore-domain potassium channels and their potential therapeutic impact. Trends in Pharmacological Sciences 29(11): 566-575.PMID: 18823665
8. Weaver, C.D., et al., A thallium-sensitive, fluorescence-based assay for detecting and characterizing potassium channel modulators in mammalian cells. J Biomol Screen, 2004. 9(8): p. 671-7.PMID: 15634793
9. Hille, B., Potassium channels in myelinated nerve. Selective permeability to small cations. J Gen Physiol, 1973. 61(6): p. 669-86.PMID: 4541077
10. Zhang, J.-H., T.D.Y. Chung, and K.R. Oldenburg, A Simple Statistical Parameter for Use in Evaluation and Validation of High Throughput Screening Assays. J Biomol Screen, 1999. 4(2), p. 67-73.PMID: 10838414
11. Malo, N., et al., Statistical practice in high-throughput screening data analysis. Nat Biotech, 2006. 24(2), p. 167-175.PMID: 16465162
12. Christine Brideau, Bert Gunter, Bill Pikounis and Andy Liaw, Improved Statistical Methods for Hit Selection in High-Throughput Screening. J Biomol Screen 2003. 8: p. 634 PMID: 14711389
Protocol
Please see the related bioassays for details of assay protocols.
Comment
Result of this screening campaign has yielded a probe compound, ML308.
Categorized Comment - additional comments and annotations
From PubChem:
Assay Cell Type: HEK293
From MLP Probe Report:
Probe count: 1
MLP Probe ML# for probe 1: ML308
PubChem Substance ID (SID) for probe 1: 134418982
PubChem Compound ID (CID) for probe 1: 56928204
Probe type for probe 1: Inhibitor
IC50/EC50 (nM) for probe 1: 130
Target for probe 1: KCNK9 (gi: 7706135)
Disease relevance for probe 1: Depression
Anti-target for probe 1: Kir2.1; hERG; KCNQ2; KCNK3;
Fold selectivity for probe 1: 7.7
NCBI Book chapter link for probe 1: http://www.ncbi.nlm.nih.gov/books/NBK133427/ (ID: 3025382)
Grant number for probe 1: MH090849-01
NCBI Book chapter title for probe 1: Development of a Selective Chemical Inhibitor for the Two-Pore Potassium Channel, KCNK9
Additional Information
Grant Number: 1 R03 MH090849-01

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