(−)‐Englerin A is a Potent and Selective Activator of TRPC4 and TRPC5 Calcium Channels

Akbulut, Yasemin; Gaunt, Hannah J.; Muraki, Katsuhiko; Ludlow, Melanie J.; Amer, Mona G.; Bruns, Alexander; Vasudev, Naveen S.; Radtke, Lea; Willot, Matthieu; Hahn, Sven; Seitz, Tobias; Ziegler, Slava; Christmann, Mathias; Beech, David J; Waldmann, Herbert

doi:10.1002/ange.201411511

Cited by 50 publications

(52 citation statements)

References 43 publications

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“…Recently, Akbulut et al showed the unexpected possibility for the rapid and selective killing of renal cancer cells (RCCs) through activation of calcium-permeable nonselective transient receptor potential canonical (TRPC) calcium channels by the sesquiterpene (−)-englerin A [1]. This compound was found to be a highly efficient, fast-acting, potent, selective, and direct stimulator of TRPC4 and TRPC5 channels.…”

Section: Discussionmentioning

confidence: 97%

Intracellular spermine blocks TRPC4 channel via electrostatic interaction with C-terminal negative amino acids

Kim

Moon

Shin

et al. 2015

Pflugers Arch - Eur J Physiol

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Transient receptor potential canonical (TRPC) 4 channels are calcium-permeable, nonselective cation channels and are widely expressed in mammalian tissue, especially in the GI tract and brain. TRPC4 channels are known to be involved in neurogenic contraction of ileal smooth muscle cells via generating cationic current after muscarinic stimulation (muscarinic cationic current (mIcat)). Polyamines exist in numerous tissues and are believed to be involved in cell proliferation, differentiation, scar formation, wound healing, and carcinogenesis. Besides, physiological polyamines are essential to maintain inward rectification of cardiac potassium channels (Kir2.1). At membrane potentials more positive than equilibrium potential, intracellular polyamines plug the cytosolic surface of the Kir2.1 so that potassium ions cannot pass through the pore. Recently, it was reported that polyamines inhibit not only cardiac potassium channels but also nonselective cation channels that mediate the generation of mIcat. Here, we report that TRPC4, a definite mIcat mediator, is inhibited by intracellular spermine with great extent. The inhibition was specific to TRPC4 and TRPC5 channels but was not effective to TRPC1/4, TRPC1/5, and TRPC3 channels. For this inhibition to occur, we found that glutamates at 728th and 729th position of TRPC4 channels are essential whereby we conclude that spermine blocks the TRPC4 channel with electrostatic interaction between negative amino acids at the C-terminus of the channel.

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Section: Discussionmentioning

confidence: 97%

Intracellular spermine blocks TRPC4 channel via electrostatic interaction with C-terminal negative amino acids

Kim

Moon

Shin

et al. 2015

Pflugers Arch - Eur J Physiol

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“…(−)‐Englerin A ( 1 ) (Figure 1), a guaiane sesquiterpene isolated from the stem bark of the East African plant Phyllanthus engleri by Beutler et al., was found to possess very potent growth inhibitory (GI) activity (GI 50 <20 n M ) against four of eight renal cancer cell lines with approximately 1000‐fold selectivity over most other cancer cell lines in the NCI‐60 panel 1. While the mechanism of action of englerin A remains to be elucidated,2 it has very recently been disclosed that 1 activates transient receptor potential canonical channels 4 and 5 (TRPC4/5) in renal cancer cells to induce cell death caused by Ca 2+ overload 3. Structurally, this molecule features an oxygen‐bridged 5‐6‐5 tricyclic system with seven contiguous stereogenic centers containing a cinnamate side chain at C6 and a glycolate fragment at C9 (englerin numbering).…”

Section: Methodsmentioning

confidence: 99%

Asymmetric Total Synthesis of (−)‐Englerin A through Catalytic Diastereo‐ and Enantioselective Carbonyl Ylide Cycloaddition

Hanari

Shimada

Kurosaki

et al. 2015

Chemistry A European J

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An asymmetric total synthesis of the guaiane sesquiterpene (−)‐englerin A, a potent and selective inhibitor of the growth of renal cancer cell lines, was accomplished. The basis of the approach is a highly diastereo‐ and enantioselective carbonyl ylide cycloaddition with an ethyl vinyl ether dipolarophile under catalysis by dirhodium(II) tetrakis[N‐tetrachlorophthaloyl‐(S)‐tert‐leucinate], [Rh2(S‐TCPTTL)4], to construct the oxabicyclo[3.2.1]octane framework with concomitant introduction of the oxygen substituent at C9 on the exo‐face. Another notable feature of the synthesis is ruthenium tetraoxide‐catalyzed chemoselective oxidative conversion of C9 ethyl ether to C9 acetate.

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“…Noncovalent, lysate-based approaches have been successfully applied to the identification of a wide range of targets, including soluble enzymes such as protein kinases [5], the lipid kinase PIKFyve [11] and many others. However, a number of therapeutically relevant target families, in particular integral membrane proteins such as ion channels and G-protein-coupled receptors, are notoriously incompatible owing to loss of their binding-competent conformation during the experimental workflow [12,13].…”

Section: Affinity-based Approachesmentioning

confidence: 99%

Identifying compound efficacy targets in phenotypic drug discovery

Schirle

Jenkins

2016

Drug Discovery Today

138

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(−)‐Englerin A is a Potent and Selective Activator of TRPC4 and TRPC5 Calcium Channels

Cited by 50 publications

References 43 publications

Intracellular spermine blocks TRPC4 channel via electrostatic interaction with C-terminal negative amino acids

Intracellular spermine blocks TRPC4 channel via electrostatic interaction with C-terminal negative amino acids

Asymmetric Total Synthesis of (−)‐Englerin A through Catalytic Diastereo‐ and Enantioselective Carbonyl Ylide Cycloaddition

Identifying compound efficacy targets in phenotypic drug discovery

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