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- EMDB-40261: DDB1/CRBN in complex with ARV-471 and the ER ligand-binding domain -

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Basic information

Entry
Database: EMDB / ID: EMD-40261
TitleDDB1/CRBN in complex with ARV-471 and the ER ligand-binding domain
Map dataMap filtered according to local resolution
Sample
  • Complex: Ternary complex of DDB1/CRBN, ARV-471, and the ER ligand-binding domain
    • Complex: DDB1/CRBN
    • Complex: Estrogen Receptor alpha ligand binding domain
KeywordsPROTAC / E3 ligase / ER / CRBN / PROTEIN BINDING
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsDigianantonio K / Drulyte I / Gough S / Bekes M / Taylor I
Funding support United States, 1 items
OrganizationGrant numberCountry
Other private United States
CitationJournal: Clin Cancer Res / Year: 2024
Title: Oral estrogen receptor PROTAC® vepdegestrant (ARV-471) is highly efficacious as monotherapy and in combination with CDK4/6 or PI3K/mTOR pathway inhibitors in preclinical ER+ breast cancer models.
Authors: Sheryl M Gough / John J Flanagan / Jessica Teh / Monica Andreoli / Emma Rousseau / Melissa Pannone / Mark Bookbinder / Ryan Willard / Kim Davenport / Elizabeth Bortolon / Gregory Cadelina / ...Authors: Sheryl M Gough / John J Flanagan / Jessica Teh / Monica Andreoli / Emma Rousseau / Melissa Pannone / Mark Bookbinder / Ryan Willard / Kim Davenport / Elizabeth Bortolon / Gregory Cadelina / Deborah Gordon / Jennifer Pizzano / Jennifer Macaluso / Leofal Soto / John Corradi / Katherine Digianantonio / Ieva Drulyte / Alicia Morgan / Connor Quinn / Miklós Békés / Caterina Ferraro / Xin Chen / Gan Wang / Hanqing Dong / Jing Wang / David R Langley / John Houston / Richard Gedrich / Ian C Taylor /
Abstract: PURPOSE: Estrogen Receptor (ER) alpha signaling is a known driver of ER-positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer. Combining endocrine therapy (ET) such ...PURPOSE: Estrogen Receptor (ER) alpha signaling is a known driver of ER-positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer. Combining endocrine therapy (ET) such as fulvestrant with CDK4/6, mTOR or PI3K inhibitors is now a central strategy for the treatment of ER+ advanced breast cancer. However, suboptimal ER inhibition and resistance resulting from ESR1 mutation dictates that new therapies are needed.
EXPERIMENTAL DESIGN: A medicinal chemistry campaign identified vepdegestrant (ARV-471), a selective, orally bioavailable, potent small molecule PROteolysis-TArgeting Chimera (PROTAC®) degrader of ER. ...EXPERIMENTAL DESIGN: A medicinal chemistry campaign identified vepdegestrant (ARV-471), a selective, orally bioavailable, potent small molecule PROteolysis-TArgeting Chimera (PROTAC®) degrader of ER. We used biochemical and intracellular target engagement assays to demonstrate the mechanism of action of vepdegestrant, and ESR1 wild-type and mutant ER+ preclinical breast cancer models to demonstrate ER degradation-mediated tumor growth inhibition.
RESULTS: Vepdegestrant induced ≥90% degradation of wild-type (WT) and mutant ER, inhibited ER-dependent breast cancer cell line proliferation in-vitro and achieved significant tumor growth ...RESULTS: Vepdegestrant induced ≥90% degradation of wild-type (WT) and mutant ER, inhibited ER-dependent breast cancer cell line proliferation in-vitro and achieved significant tumor growth inhibition (TGI) (87-123%) in MCF7 orthotopic xenograft models, better than the ET agent fulvestrant (31-80% TGI). In the hormone-independent ER Y537S patient derived xenograft (PDX) breast cancer model ST941/HI, vepdegestrant achieved tumor regressions and was similarly efficacious in the ST941/HI/PBR palbociclib-resistant model (102% TGI). Vepdegestrant induced robust tumor regressions in combination with each of the CDK4/6 inhibitors palbociclib, abemaciclib, and ribociclib, the mTOR inhibitor everolimus, and the PI3K inhibitors alpelisib and inavolisib.
CONCLUSIONS: Vepdegestrant achieved greater ER degradation in-vivo compared to fulvestrant, which correlated with improved tumor growth inhibition, suggesting vepdegestrant could be a more effective ...CONCLUSIONS: Vepdegestrant achieved greater ER degradation in-vivo compared to fulvestrant, which correlated with improved tumor growth inhibition, suggesting vepdegestrant could be a more effective backbone ET for patients with ER+/HER2- breast cancer.
History
DepositionMar 31, 2023-
Header (metadata) releaseMay 29, 2024-
Map releaseMay 29, 2024-
UpdateJun 12, 2024-
Current statusJun 12, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_40261.png

Downloads & links

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Map

FileDownload / File: emd_40261.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMap filtered according to local resolution
Voxel sizeX=Y=Z: 1.3995 Å
Density
Contour LevelBy AUTHOR: 0.08
Minimum - Maximum-1.0436109 - 1.9463576
Average (Standard dev.)0.0008971638 (±0.026171967)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 335.88 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_40261_msk_1.map
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AxesZYX

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Mask #2

Fileemd_40261_msk_2.map
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Additional map: Sharpened map

Fileemd_40261_additional_1.map
AnnotationSharpened map
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Additional map: Unsharpened map

Fileemd_40261_additional_2.map
AnnotationUnsharpened map
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Half map: Half map A

Fileemd_40261_half_map_1.map
AnnotationHalf map A
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Half map: Half map B

Fileemd_40261_half_map_2.map
AnnotationHalf map B
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Sample components

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Entire : Ternary complex of DDB1/CRBN, ARV-471, and the ER ligand-binding ...

EntireName: Ternary complex of DDB1/CRBN, ARV-471, and the ER ligand-binding domain
Components
  • Complex: Ternary complex of DDB1/CRBN, ARV-471, and the ER ligand-binding domain
    • Complex: DDB1/CRBN
    • Complex: Estrogen Receptor alpha ligand binding domain

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Supramolecule #1: Ternary complex of DDB1/CRBN, ARV-471, and the ER ligand-binding ...

SupramoleculeName: Ternary complex of DDB1/CRBN, ARV-471, and the ER ligand-binding domain
type: complex / ID: 1 / Parent: 0
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #2: DDB1/CRBN

SupramoleculeName: DDB1/CRBN / type: complex / ID: 2 / Parent: 1
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: Estrogen Receptor alpha ligand binding domain

SupramoleculeName: Estrogen Receptor alpha ligand binding domain / type: complex / ID: 3 / Parent: 1
Source (natural)Organism: Homo sapiens (human)

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.3
Component:
ConcentrationFormulaName
50.0 mMHepeshepes
50.0 mMNaClsodium chloride
1.0 mMTCEP
VitrificationCryogen name: ETHANE / Instrument: SPOTITON / Details: SPT labtech chameleon.

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: TFS Selectris X / Energy filter - Slit width: 10 eV
DetailsThe microscope was equipped with an E-CFEG. Fringe-free imaging and aberration-free image shifts were used during data collection. Nominal pixel size for 130,000x - 0.96 A/px, calibrated - 0.933 A/px.
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Number grids imaged: 1 / Number real images: 5321 / Average exposure time: 6.32 sec. / Average electron dose: 50.5 e/Å2
Details: Falcon 4i Detector operated in Electron-Event Representation mode was used to record the images.
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.75 µm / Nominal defocus min: 0.75 µm / Nominal magnification: 130000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1081032
Startup modelType of model: OTHER / Details: ab initio cryoSPARC v3.3.2
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 116673
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.3.2)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.3.2)
Final 3D classificationNumber classes: 3 / Software - Name: cryoSPARC (ver. 3.3.2)
Details: 3D Variability Analysis (with a local mask surrounding the CRBN-ER region and the resolution filtered to 10 A) was used to select the best subset of particles.
FSC plot (resolution estimation)

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