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- PDB-9moe: Preclinical and clinical evaluation of a novel TRPA1 antagonist L... -

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Basic information

Entry
Database: PDB / ID: 9moe
TitlePreclinical and clinical evaluation of a novel TRPA1 antagonist LY3526318
ComponentsTransient receptor potential cation channel subfamily A member 1
KeywordsMEMBRANE PROTEIN / Pain receptor / TrpA1 / ion channel / ligand gating
Function / homology
Function and homology information


cellular response to food / temperature-gated cation channel activity / stereocilium bundle / detection of chemical stimulus involved in sensory perception of pain / thermoception / TRP channels / response to pain / intracellularly gated calcium channel activity / detection of mechanical stimulus involved in sensory perception of pain / monoatomic ion transport ...cellular response to food / temperature-gated cation channel activity / stereocilium bundle / detection of chemical stimulus involved in sensory perception of pain / thermoception / TRP channels / response to pain / intracellularly gated calcium channel activity / detection of mechanical stimulus involved in sensory perception of pain / monoatomic ion transport / sensory perception of pain / response to cold / calcium ion transmembrane transport / calcium channel activity / cellular response to hydrogen peroxide / intracellular calcium ion homeostasis / channel activity / protein homotetramerization / cell surface receptor signaling pathway / response to xenobiotic stimulus / identical protein binding / plasma membrane
Similarity search - Function
: / Ankyrin repeat / Ankyrin repeats (3 copies) / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
: / Transient receptor potential cation channel subfamily A member 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.7 Å
AuthorsNie, S.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Pain / Year: 2025
Title: Preclinical and clinical evaluation of a novel TRPA1 antagonist LY3526318.
Authors: Lisa M Broad / Jeffrey G Suico / P Kellie Turner / Si Nie / Kirk W Johnson / Helen E Sanger / Lindsay A Wegiel / David C Sperry / David Remick / Magdalene Moran / Sam Malekiani / Donato Del ...Authors: Lisa M Broad / Jeffrey G Suico / P Kellie Turner / Si Nie / Kirk W Johnson / Helen E Sanger / Lindsay A Wegiel / David C Sperry / David Remick / Magdalene Moran / Sam Malekiani / Donato Del Camino / Xinyuan Wu / Jayhong A Chong / Nathaniel T Blair / August V Wilke /
Abstract: The transient receptor potential cation channel member A1 (TRPA1) is heavily implicated in nociceptive signaling in both physiological and pathological pain states. However, it has been challenging ...The transient receptor potential cation channel member A1 (TRPA1) is heavily implicated in nociceptive signaling in both physiological and pathological pain states. However, it has been challenging to develop TRPA1 antagonists with appropriate properties to advance into clinical development. Herein, we describe the preclinical characterization and early clinical development of LY3526318, a potent, selective, and orally bioavailable TRPA1 antagonist. In vitro studies showed that LY3526318 reversibly inhibited recombinant TRPA1 channels with nanomolar potency that was conserved across species. LY3526318 also inhibited the function of native human and rat TRPA1 channels, including nociceptive dorsal root ganglion neuronal TRPA1 channels. In vivo studies showed that LY3526318 blocked formalin-evoked flinching behaviors and chronic Freund adjuvant-induced cold hypersensitivity in rats. Only male rats were used in these studies. Initial phase 1, single- and multiple-ascending dose studies evaluating pharmacokinetic and safety parameters of LY3526318 revealed a suboptimal pharmacokinetic profile leading to the development and study of a spray-dried dispersion (SDD) formulation of LY3526318. When dosed once daily at 250 mg, LY3526318-SDD showed a tmax of 4 hours and t1/2 of 12 hours, maintaining plasma exposures demonstrated to engage the TRPA1 target. Adverse events were transient and mild across all phase 1 studies. In summary, LY3526318 blocked TRPA1 in vitro and in vivo, inhibited behavioral signs of enhanced nociception in animal models, and was safe and well tolerated in phase 1 clinical studies, with LY3526318-SDD displaying an appropriate pharmacokinetic profile to advance to proof-of-concept studies in patients with chronic pain.
History
DepositionDec 26, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 21, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Transient receptor potential cation channel subfamily A member 1
B: Transient receptor potential cation channel subfamily A member 1
D: Transient receptor potential cation channel subfamily A member 1
E: Transient receptor potential cation channel subfamily A member 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)513,0248
Polymers510,7984
Non-polymers2,2264
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein
Transient receptor potential cation channel subfamily A member 1 / Ankyrin-like with transmembrane domains protein 1 / Transformation-sensitive protein p120 / p120 / ...Ankyrin-like with transmembrane domains protein 1 / Transformation-sensitive protein p120 / p120 / Wasabi receptor


Mass: 127699.586 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TRPA1, ANKTM1 / Production host: Homo sapiens (human) / References: UniProt: O75762
#2: Chemical
ChemComp-A1BNO / (2S)-2-{3-methyl-1-[(3-methyl-1,2,4-oxadiazol-5-yl)methyl]-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl}-N-{6-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-2-yl}propanamide


Mass: 556.457 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C23H19F3N10O4 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: tetrameric ion channel TrpA1 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.684 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
Details: 20 mM HEPES, pH 8, 150 mM NaCl, 0.5 mM TCEP and 0.01% LMNG
SpecimenConc.: 2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 600 nm / C2 aperture diameter: 70 µm
Image recordingElectron dose: 18 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 200000 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 39.53 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.003317986
ELECTRON MICROSCOPYf_angle_d0.465224382
ELECTRON MICROSCOPYf_chiral_restr0.03792861
ELECTRON MICROSCOPYf_plane_restr0.00392950
ELECTRON MICROSCOPYf_dihedral_angle_d3.7182458

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