Identification of a dihydropyridine scaffold that blocks ryanodine receptors

Gihan S. Gunaratne; Robyn T. Rebbeck; Lindsey M. McGurran; Yasheng Yan; Thiago Arzua; Talia Frolkis; Daniel J. Sprague; Xiaowen Bai; Razvan L. Cornea; Timothy F. Walseth; Jonathan S. Marchant

doi:10.1016/j.isci.2021.103706

Identification of a dihydropyridine scaffold that blocks ryanodine receptors

Gihan S. Gunaratne, Robyn T. Rebbeck, Lindsey M. McGurran, Yasheng Yan, Thiago Arzua, Talia Frolkis, Daniel J. Sprague, Xiaowen Bai, Razvan L. Cornea, Timothy F. Walseth, Jonathan S. Marchant

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Abstract

Ryanodine receptors (RyRs) are large, intracellular ion channels that control Ca²⁺ release from the sarco/endoplasmic reticulum. Dysregulation of RyRs in skeletal muscle, heart, and brain has been implicated in various muscle pathologies, arrhythmia, heart failure, and Alzheimer's disease. Therefore, there is considerable interest in therapeutically targeting RyRs to normalize Ca²⁺ homeostasis in scenarios involving RyR dysfunction. Here, a simple invertebrate screening platform was used to discover new chemotypes targeting RyRs. The approach measured Ca²⁺ signals evoked by cyclic adenosine 5′-diphosphate ribose, a second messenger that sensitizes RyRs. From a 1,534-compound screen, FLI-06 (currently described as a Notch “inhibitor”) was identified as a potent blocker of RyR activity. Two closely related tyrosine kinase inhibitors that stimulate and inhibit Ca²⁺ release through RyRs were also resolved. Therefore, this simple screen yielded RyR scaffolds tractable for development and revealed an unexpected linkage between RyRs and trafficking events in the early secretory pathway.

Original language	English (US)
Article number	103706
Journal	iScience
Volume	25
Issue number	1
DOIs	https://doi.org/10.1016/j.isci.2021.103706
State	Published - Jan 21 2022

Bibliographical note

Funding Information:
This work was supported by NIH GM088790 (to J.S.M.) and HL138539 (to R.L.C.).

Funding Information:
This work was supported by NIH GM088790 (to J.S.M.) and HL138539 (to R.L.C.). G.S.G. R.T.R. L.M.M. Y.Y. T.A. T.F. and D.J.S. acquired data and interpreted results. G.S.G. and J.S.M. prepared the manuscript draft. G.S.G. R.T.R. Y.Y. X.B. R.L.C. T.F.W. and J.S.M. reviewed and edited the manuscript. All authors have read and agreed to publish the submitted manuscript. RLC holds equity in and serves as an executive officer for Photonic Pharma LLC. This relationship has been reviewed and managed by the University of Minnesota. Photonic Pharma had no role in this study, except to provide access to instrumentation. G.S.G. R.T.R. L.M.M. Y.Y. T.A. T.F. D.J.S. X.B. T.F.W. and J.S.M. have no conflicts of interest to disclose. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. One or more of the authors of this paper self-identifies as living with a disability.

Publisher Copyright:
© 2021 The Author(s)

Keywords

Biochemistry
Cell biology
Molecular physiology
Natural product chemistry

PubMed: MeSH publication types

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title = "Identification of a dihydropyridine scaffold that blocks ryanodine receptors",

abstract = "Ryanodine receptors (RyRs) are large, intracellular ion channels that control Ca2+ release from the sarco/endoplasmic reticulum. Dysregulation of RyRs in skeletal muscle, heart, and brain has been implicated in various muscle pathologies, arrhythmia, heart failure, and Alzheimer's disease. Therefore, there is considerable interest in therapeutically targeting RyRs to normalize Ca2+ homeostasis in scenarios involving RyR dysfunction. Here, a simple invertebrate screening platform was used to discover new chemotypes targeting RyRs. The approach measured Ca2+ signals evoked by cyclic adenosine 5′-diphosphate ribose, a second messenger that sensitizes RyRs. From a 1,534-compound screen, FLI-06 (currently described as a Notch “inhibitor”) was identified as a potent blocker of RyR activity. Two closely related tyrosine kinase inhibitors that stimulate and inhibit Ca2+ release through RyRs were also resolved. Therefore, this simple screen yielded RyR scaffolds tractable for development and revealed an unexpected linkage between RyRs and trafficking events in the early secretory pathway.",

keywords = "Biochemistry, Cell biology, Molecular physiology, Natural product chemistry",

author = "Gunaratne, {Gihan S.} and Rebbeck, {Robyn T.} and McGurran, {Lindsey M.} and Yasheng Yan and Thiago Arzua and Talia Frolkis and Sprague, {Daniel J.} and Xiaowen Bai and Cornea, {Razvan L.} and Walseth, {Timothy F.} and Marchant, {Jonathan S.}",

note = "Funding Information: This work was supported by NIH GM088790 (to J.S.M.) and HL138539 (to R.L.C.). Funding Information: This work was supported by NIH GM088790 (to J.S.M.) and HL138539 (to R.L.C.). G.S.G. R.T.R. L.M.M. Y.Y. T.A. T.F. and D.J.S. acquired data and interpreted results. G.S.G. and J.S.M. prepared the manuscript draft. G.S.G. R.T.R. Y.Y. X.B. R.L.C. T.F.W. and J.S.M. reviewed and edited the manuscript. All authors have read and agreed to publish the submitted manuscript. RLC holds equity in and serves as an executive officer for Photonic Pharma LLC. This relationship has been reviewed and managed by the University of Minnesota. Photonic Pharma had no role in this study, except to provide access to instrumentation. G.S.G. R.T.R. L.M.M. Y.Y. T.A. T.F. D.J.S. X.B. T.F.W. and J.S.M. have no conflicts of interest to disclose. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community. One or more of the authors of this paper self-identifies as living with a disability. Publisher Copyright: {\textcopyright} 2021 The Author(s)",

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AU - Arzua, Thiago

AU - Frolkis, Talia

AU - Sprague, Daniel J.

AU - Bai, Xiaowen

AU - Cornea, Razvan L.

AU - Walseth, Timothy F.

AU - Marchant, Jonathan S.

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N2 - Ryanodine receptors (RyRs) are large, intracellular ion channels that control Ca2+ release from the sarco/endoplasmic reticulum. Dysregulation of RyRs in skeletal muscle, heart, and brain has been implicated in various muscle pathologies, arrhythmia, heart failure, and Alzheimer's disease. Therefore, there is considerable interest in therapeutically targeting RyRs to normalize Ca2+ homeostasis in scenarios involving RyR dysfunction. Here, a simple invertebrate screening platform was used to discover new chemotypes targeting RyRs. The approach measured Ca2+ signals evoked by cyclic adenosine 5′-diphosphate ribose, a second messenger that sensitizes RyRs. From a 1,534-compound screen, FLI-06 (currently described as a Notch “inhibitor”) was identified as a potent blocker of RyR activity. Two closely related tyrosine kinase inhibitors that stimulate and inhibit Ca2+ release through RyRs were also resolved. Therefore, this simple screen yielded RyR scaffolds tractable for development and revealed an unexpected linkage between RyRs and trafficking events in the early secretory pathway.

AB - Ryanodine receptors (RyRs) are large, intracellular ion channels that control Ca2+ release from the sarco/endoplasmic reticulum. Dysregulation of RyRs in skeletal muscle, heart, and brain has been implicated in various muscle pathologies, arrhythmia, heart failure, and Alzheimer's disease. Therefore, there is considerable interest in therapeutically targeting RyRs to normalize Ca2+ homeostasis in scenarios involving RyR dysfunction. Here, a simple invertebrate screening platform was used to discover new chemotypes targeting RyRs. The approach measured Ca2+ signals evoked by cyclic adenosine 5′-diphosphate ribose, a second messenger that sensitizes RyRs. From a 1,534-compound screen, FLI-06 (currently described as a Notch “inhibitor”) was identified as a potent blocker of RyR activity. Two closely related tyrosine kinase inhibitors that stimulate and inhibit Ca2+ release through RyRs were also resolved. Therefore, this simple screen yielded RyR scaffolds tractable for development and revealed an unexpected linkage between RyRs and trafficking events in the early secretory pathway.

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KW - Cell biology

KW - Molecular physiology

KW - Natural product chemistry

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Identification of a dihydropyridine scaffold that blocks ryanodine receptors

Abstract

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