Selective inhibition of the K ir2 family of inward rectifier potassium channels by a small molecule probe: The discovery, SAR, and pharmacological characterization of ML133

Hao Ran Wang, Meng Wu, Haibo Yu, Shunyou Long, Amy Stevens, Darren W. Engers, Henry Sackin, J. Scott Daniels, Eric S. Dawson, Corey R. Hopkins, Craig W. Lindsley, Min Li, Owen B. McManus

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Abstract

The K ir inward rectifying potassium channels have a broad tissue distribution and are implicated in a variety of functional roles. At least seven classes (K ir1-K ir7) of structurally related inward rectifier potassium channels are known, and there are no selective small molecule tools to study their function. In an effort to develop selective K ir2.1 inhibitors, we performed a high-throughput screen (HTS) of more than 300,000 small molecules within the MLPCN for modulators of K ir2.1 function. Here we report one potent K ir2.1 inhibitor, ML133, which inhibits K ir2.1 with an IC 50 of 1.8 μM at pH 7.4 and 290 nM at pH 8.5 but exhibits little selectivity against other members of Kir2.x family channels. However, ML133 has no effect on K ir1.1 (IC 50 > 300 μM) and displays weak activity for K ir4.1 (76 μM) and K ir7.1 (33 μM), making ML133 the most selective small molecule inhibitor of the K ir family reported to date. Because of the high homology within the K ir2 family-the channels share a common design of a pore region flanked by two transmembrane domains-identification of site(s) critical for isoform specificity would be an important basis for future development of more specific and potent K ir inhibitors. Using chimeric channels between K ir2.1 and K ir1.1 and site-directed mutagenesis, we have identified D172 and I176 within M2 segment of K ir2.1 as molecular determinants critical for the potency of ML133 mediated inhibition. Double mutation of the corresponding residues of K ir1.1 to those of K ir2.1 (N171D and C175I) transplants ML133 inhibition to K ir1.1. Together, the combination of a potent, K ir2 family selective inhibitor and identification of molecular determinants for the specificity provides both a tool and a model system to enable further mechanistic studies of modulation of K ir2 inward rectifier potassium channels.

Original languageEnglish (US)
Pages (from-to)845-856
Number of pages12
JournalACS Chemical Biology
Volume6
Issue number8
DOIs
StatePublished - Aug 19 2011

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Inwardly Rectifying Potassium Channel
Pharmacology
Molecules
Potassium Channels
Tissue Distribution
Site-Directed Mutagenesis
Mutagenesis
Transplants
Protein Isoforms
Modulators
Mutation
Throughput
Modulation
Tissue

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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Selective inhibition of the K ir2 family of inward rectifier potassium channels by a small molecule probe : The discovery, SAR, and pharmacological characterization of ML133. / Wang, Hao Ran; Wu, Meng; Yu, Haibo; Long, Shunyou; Stevens, Amy; Engers, Darren W.; Sackin, Henry; Daniels, J. Scott; Dawson, Eric S.; Hopkins, Corey R.; Lindsley, Craig W.; Li, Min; McManus, Owen B.

In: ACS Chemical Biology, Vol. 6, No. 8, 19.08.2011, p. 845-856.

Research output: Contribution to journalArticle

Wang, HR, Wu, M, Yu, H, Long, S, Stevens, A, Engers, DW, Sackin, H, Daniels, JS, Dawson, ES, Hopkins, CR, Lindsley, CW, Li, M & McManus, OB 2011, 'Selective inhibition of the K ir2 family of inward rectifier potassium channels by a small molecule probe: The discovery, SAR, and pharmacological characterization of ML133', ACS Chemical Biology, vol. 6, no. 8, pp. 845-856. https://doi.org/10.1021/cb200146a
Wang, Hao Ran ; Wu, Meng ; Yu, Haibo ; Long, Shunyou ; Stevens, Amy ; Engers, Darren W. ; Sackin, Henry ; Daniels, J. Scott ; Dawson, Eric S. ; Hopkins, Corey R. ; Lindsley, Craig W. ; Li, Min ; McManus, Owen B. / Selective inhibition of the K ir2 family of inward rectifier potassium channels by a small molecule probe : The discovery, SAR, and pharmacological characterization of ML133. In: ACS Chemical Biology. 2011 ; Vol. 6, No. 8. pp. 845-856.
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abstract = "The K ir inward rectifying potassium channels have a broad tissue distribution and are implicated in a variety of functional roles. At least seven classes (K ir1-K ir7) of structurally related inward rectifier potassium channels are known, and there are no selective small molecule tools to study their function. In an effort to develop selective K ir2.1 inhibitors, we performed a high-throughput screen (HTS) of more than 300,000 small molecules within the MLPCN for modulators of K ir2.1 function. Here we report one potent K ir2.1 inhibitor, ML133, which inhibits K ir2.1 with an IC 50 of 1.8 μM at pH 7.4 and 290 nM at pH 8.5 but exhibits little selectivity against other members of Kir2.x family channels. However, ML133 has no effect on K ir1.1 (IC 50 > 300 μM) and displays weak activity for K ir4.1 (76 μM) and K ir7.1 (33 μM), making ML133 the most selective small molecule inhibitor of the K ir family reported to date. Because of the high homology within the K ir2 family-the channels share a common design of a pore region flanked by two transmembrane domains-identification of site(s) critical for isoform specificity would be an important basis for future development of more specific and potent K ir inhibitors. Using chimeric channels between K ir2.1 and K ir1.1 and site-directed mutagenesis, we have identified D172 and I176 within M2 segment of K ir2.1 as molecular determinants critical for the potency of ML133 mediated inhibition. Double mutation of the corresponding residues of K ir1.1 to those of K ir2.1 (N171D and C175I) transplants ML133 inhibition to K ir1.1. Together, the combination of a potent, K ir2 family selective inhibitor and identification of molecular determinants for the specificity provides both a tool and a model system to enable further mechanistic studies of modulation of K ir2 inward rectifier potassium channels.",
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AU - Yu, Haibo

AU - Long, Shunyou

AU - Stevens, Amy

AU - Engers, Darren W.

AU - Sackin, Henry

AU - Daniels, J. Scott

AU - Dawson, Eric S.

AU - Hopkins, Corey R.

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AU - Li, Min

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