scholarly journals Retracted: Addition of a single methyl group to a small molecule sodium channel inhibitor introduces a new mode of gating modulation, by L Wang, SG Zellmer, DM Printzenhoff and NA Castle. British Journal of Pharmacology, volume 172(20): 4905-4918, publish

2018 ◽  
Vol 175 (13) ◽  
pp. 2712-2712
Keyword(s):  
British Journal ◽  
Sodium Channel ◽  
Small Molecule ◽  
Methyl Group ◽  
Gating Modulation

scholarly journals Retracted:Addition of a single methyl group to a small molecule sodium channel inhibitor introduces a new mode of gating modulation

2015 ◽  
Vol 172 (20) ◽  
pp. 4905-4918 ◽  
Author(s):  
Lingxin Wang ◽  
Shannon G. Zellmer ◽  
David M. Printzenhoff ◽  
Neil A. Castle
Keyword(s):  
Sodium Channel ◽  
Small Molecule ◽  
Methyl Group ◽  
Gating Modulation

scholarly journals New Insights into 4-Anilinoquinazolines as Inhibitors of Cardiac Troponin I–Interacting Kinase (TNNi3K)

Molecules ◽  
2020 ◽  
Vol 25 (7) ◽  
pp. 1697 ◽  
Author(s):  
Christopher R. M. Asquith ◽  
Tuomo Laitinen ◽  
Carrow I. Wells ◽  
Graham J. Tizzard ◽  
William J. Zuercher
Keyword(s):  
Small Molecule ◽  
Cardiac Troponin ◽  
Kinase Activity ◽  
Troponin I ◽  
Negative Control ◽  
Cardiac Troponin I ◽  
Binding Motif ◽  
Binding Region ◽  
Methyl Group ◽  
Structure Activity

We report the synthesis of several related 4-anilinoquinazolines as inhibitors of cardiac troponin I–interacting kinase (TNNi3K). These close structural analogs of 3-((6,7-dimethoxyquinazolin-4-yl)amino)-4-(dimethylamino)-N-methylbenzenesulfonamide (GSK114) provide new understanding of structure–activity relationships between the 4-anilinoquinazoline scaffold and TNNi3K inhibition. Through a small focused library of inhibitors, we observed that the N-methylbenzenesulfonamide was driving the potency in addition to the more traditional quinazoline hinge-binding motif. We also identified a compound devoid of TNNi3K kinase activity due to the addition of a methyl group in the hinge binding region. This compound could serve as a negative control in the study of TNNi3K biology. Small molecule crystal structures of several quinazolines have been solved, supporting observations made about overall conformation and TNNi3K inhibition.

scholarly journals Evidence that toxin resistance in poison birds and frogs is not rooted in sodium channel mutations and may rely on “toxin sponge” proteins

2021 ◽  
Vol 153 (9) ◽  
Author(s):  
Fayal Abderemane-Ali ◽  
Nathan D. Rossen ◽  
Megan E. Kobiela ◽  
Robert A. Craig ◽  
Catherine E. Garrison ◽  
...  
Keyword(s):  
Ion Channel ◽  
Sodium Channel ◽  
Small Molecule ◽  
Resistance Mechanism ◽  
Poison Frog ◽  
Poison Frogs ◽  
Toxin Resistance ◽  
Voltage Gated ◽  
Primary Driver ◽  
Toxin Sequestration

Many poisonous organisms carry small-molecule toxins that alter voltage-gated sodium channel (NaV) function. Among these, batrachotoxin (BTX) from Pitohui poison birds and Phyllobates poison frogs stands out because of its lethality and unusual effects on NaV function. How these toxin-bearing organisms avoid autointoxication remains poorly understood. In poison frogs, a NaV DIVS6 pore-forming helix N-to-T mutation has been proposed as the BTX resistance mechanism. Here, we show that this variant is absent from Pitohui and poison frog NaVs, incurs a strong cost compromising channel function, and fails to produce BTX-resistant channels in poison frog NaVs. We also show that captivity-raised poison frogs are resistant to two NaV-directed toxins, BTX and saxitoxin (STX), even though they bear NaVs sensitive to both. Moreover, we demonstrate that the amphibian STX “toxin sponge” protein saxiphilin is able to protect and rescue NaVs from block by STX. Taken together, our data contradict the hypothesis that BTX autoresistance is rooted in the DIVS6 N→T mutation, challenge the idea that ion channel mutations are a primary driver of toxin resistance, and suggest the possibility that toxin sequestration mechanisms may be key for protecting poisonous species from the action of small-molecule toxins.

scholarly journals Abstract 2001: Inhibiting voltage-gated sodium channel activity in medullary thyroid cancer using small molecule compounds

2019 ◽  
Author(s):  
Paras Ahuja ◽  
Rachael Guenter ◽  
Jaden Cowan ◽  
Yazen Shihab ◽  
Jason Whitt ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Sodium Channel ◽  
Small Molecule ◽  
Medullary Thyroid Cancer ◽  
Channel Activity ◽  
Voltage Gated Sodium Channel ◽  
Medullary Thyroid ◽  
Voltage Gated

scholarly journals Abstract 2001: Inhibiting voltage-gated sodium channel activity in medullary thyroid cancer using small molecule compounds

2019 ◽  
Author(s):  
Paras Ahuja ◽  
Rachael Guenter ◽  
Jaden Cowan ◽  
Yazen Shihab ◽  
Jason Whitt ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Sodium Channel ◽  
Small Molecule ◽  
Medullary Thyroid Cancer ◽  
Channel Activity ◽  
Voltage Gated Sodium Channel ◽  
Medullary Thyroid ◽  
Voltage Gated

scholarly journals Novel Inhibitors of Nicotinamide-N-Methyltransferase for the Treatment of Metabolic Disorders

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 991
Author(s):  
Aimo Kannt ◽  
Sridharan Rajagopal ◽  
Mahanandeesha S. Hallur ◽  
Indu Swamy ◽  
Rajendra Kristam ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Recent Work ◽  
Small Molecule ◽  
Metabolic Disorders ◽  
Metabolic Diseases ◽  
Binding Modes ◽  
Methyl Group ◽  
X Ray ◽  
Adenosyl Methionine

Nicotinamide-N-methyltransferase (NNMT) is a cytosolic enzyme catalyzing the transfer of a methyl group from S-adenosyl-methionine (SAM) to nicotinamide (Nam). It is expressed in many tissues including the liver, adipose tissue, and skeletal muscle. Its expression in several cancer cell lines has been widely discussed in the literature, and recent work established a link between NNMT expression and metabolic diseases. Here we describe our approach to identify potent small molecule inhibitors of NNMT featuring different binding modes as elucidated by X-ray crystallographic studies.

scholarly journals Pharmacologic Characterization of AMG8379, a Potent and Selective Small Molecule Sulfonamide Antagonist of the Voltage-Gated Sodium Channel NaV1.7

2017 ◽  
Vol 362 (1) ◽  
pp. 146-160 ◽  
Author(s):  
Thomas J. Kornecook ◽  
Ruoyuan Yin ◽  
Stephen Altmann ◽  
Xuhai Be ◽  
Virginia Berry ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Small Molecule ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated

scholarly journals Sodium channel toxin-resistance mutations do not govern batrachotoxin (BTX) autoresistance in poison birds and frogs

2020 ◽  
Author(s):  
Fayal Abderemane-Ali ◽  
Nathan D. Rossen ◽  
Megan E. Kobiela ◽  
Robert A. Craig ◽  
Catherine E. Garrison ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Small Molecule ◽  
Resistance Mechanism ◽  
Resistance Mutations ◽  
Poison Frog ◽  
Poison Frogs ◽  
Toxin Resistance ◽  
Voltage Gated ◽  
Channel Function ◽  
Toxin Sequestration

AbstractPoisonous organisms carry small molecule toxins that alter voltage-gated sodium channel (Na✓) function. Among these, batrachotoxin (BTX) from Pitohui toxic birds and Phyllobates poison frogs, stands out because of its lethality and unusual effects on Nav function. How these toxin-bearing organisms avoid autointoxication remains poorly understood. In poison frogs, a Nav DIVS6 pore-forming helix N→T mutation has been proposed as the BTX resistance mechanism. Here, we show that this variant is absent from Pitohui and poison frog Navs, incurs a strong cost that compromises channel function, and fails to produce BTX-resistant channels when tested in the context of poison frog Navs. We further show that captive-raised poison frogs are BTX resistant, even though they bear BTX-sensitive Navs. Hence, our data refute the hypothesis that BTX autoresistance is rooted in Nav mutations and instead suggest that more generalizable mechanisms such as toxin sequestration act to protect BTX-bearing species from autointoxication.

Sign in / Sign up

Export Citation Format

Share Document