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: Elena Makhina Ph.D., University of Pittsburgh
Network: Molecular Libraries Probe Production Centers Network (MLPCN)
Grant Proposal Number: 1 R03 DA026212-01
Grant Proposal PI: Elena Makhina Ph.D., University of Pittsburgh
Assay Implementation: Meng Wu Ph.D., Hao-ran Wang Ph.D., Haibo Yu Ph.D., Elena Makhina Ph.D., Jia Xu Ph.D., Eric S Dawson Ph.D., Corey R Hopkins Ph.D., Craig W Lindsley Ph.D., Owen B McManus Ph.D., and Min Li Ph.D..



Name: Summary of probe development for inhibitors/blockers of inward-rectifying potassium ion channel Kir2.1


Description:

Potassium (K+) channels are well recognized as a target in the treatment of cardiovascular, neurological, renal and metabolic disorders [1, 2]. However, the number of ion channel drugs is strikingly small, compared to the number of ion channel genes. Most of the known K+ channel modulators lack potency and specificity. The reason for slow development of K+ channel drugs lies largely in the low capacity and high cost of electrophysiology-based screening techniques.

The overall goal of the project is to discover inhibitors of the Kir2.1 channel with EC50 < 1 uM. Identified compounds will serve as both a basis for development of clinical K+ channel drugs, and as a basic study of K+ channel physiology with novel mechanisms of action.

The Kir2.1 channel (KCNJ2) is a member of inwardly-rectifying potassium channels, expressing two transmembrane-spanning segments, flanking a conserved pore region. Inward rectifier K+ channels pass prominent inward currents, and mediate the cardiac inwardly-rectifying potassium current (IK1) [3], while outward currents are largely blocked. The rectification process is mediated through blocking of the channel pore by intracellular Mg2+ and polyamines, and is specific for individual Kir subtypes [4, 5]. Specific modulators of the Kir2.1 channel serve as leads for development of anti-arrhythmic drugs, including drugs for treatment of short- and long-QT syndromes, as well as for the treatment of Andersen syndrome. Several Kir2.1 inhibitor candidates have been discovered [6] [7], i.e. Chlorpromazine, Celastrol, and Gambogic acid. However, a highly specific, high potency small molecule is still in need, not only for the mechanistic probing of the ion channel activities, but also to generate leads for therapeutics for related diseases.

This BioAssay summarize the efforts of developing small molecular inhibitors to the inward-rectifying potassium ion channel Kir2.1.

References:

1. Kaczorowski, G.J., et al., Ion Channels as Drug Targets: The Next GPCRs. J. Gen. Physiol., 2008. 131(5): p. 399-405. PMID: 18411331
2. Garcia, M.L. and G.J. Kaczorowski, Potassium Channels as Targets for Therapeutic Intervention. Sci. STKE, 2005. 2005(302): p. pe46-. PMID: 16174819
3. Lopatin, A.N. and C.G. Nichols, Inward Rectifiers in the Heart: An Update on IK1. Journal of Molecular and Cellular Cardiology, 2001. 33(4): p. 625-638. PMID: 11273717
4. Ficker, E., et al., Spermine and spermidine as gating molecules for inward rectifier K+ channels. Science, 1994. 266(5187): p. 1068-1072. PMID: 7973666
5. Dhamoon, A.S., et al., Unique Kir2.x Properties Determine Regional and Species Differences in the Cardiac Inward Rectifier K+ Current. Circ Res, 2004. 94(10): p. 1332-1339. PMID: 15087421
6. Sun, H., et al., Chronic Inhibition of Cardiac Kir2.1 and hERG Potassium Channels by Celastrol with Dual Effects on Both Ion Conductivity and Protein Trafficking. J. Biol. Chem., 2006. 281(9): p. 5877-5884. PMID: 16407206
7. Zaks-Makhina, E., et al., Novel Neuroprotective K+ Channel Inhibitor Identified by High-Throughput Screening in Yeast. Mol Pharmacol, 2004. 65(1): p. 214-219. PMID: 14722253

Please see the related BioAssays (i.e. AID 1672) for details of the assay protocol.

For the probes, the activity score is assigned as 100.

Result of this screening campaign has yielded a probe compound, ML133.

Grant Number: 1 R03 DA026212-01