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Yorodumi- EMDB-40261: DDB1/CRBN in complex with ARV-471 and the ER ligand-binding domain -
+Open data
-Basic information
Entry | Database: EMDB / ID: EMD-40261 | |||||||||
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Title | DDB1/CRBN in complex with ARV-471 and the ER ligand-binding domain | |||||||||
Map data | Map filtered according to local resolution | |||||||||
Sample |
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Keywords | PROTAC / E3 ligase / ER / CRBN / PROTEIN BINDING | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.7 Å | |||||||||
Authors | Digianantonio K / Drulyte I / Gough S / Bekes M / Taylor I | |||||||||
Funding support | United States, 1 items
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Citation | Journal: 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 / Debbie 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 has become a central strategy in the treatment of ER+ advanced breast cancer. However, suboptimal ER inhibition and resistance resulting from the ESR1 mutation dictates that new therapies are needed. EXPERIMENTAL DESIGN: A medicinal chemistry campaign identified vepdegestrant (ARV-471), a selective, orally bioavailable, and potent small molecule PROteolysis-TArgeting Chimera (PROTAC) degrader of ...EXPERIMENTAL DESIGN: A medicinal chemistry campaign identified vepdegestrant (ARV-471), a selective, orally bioavailable, and 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 (WT) and mutant ER+ preclinical breast cancer models to demonstrate ER degradation-mediated tumor growth inhibition (TGI). RESULTS: Vepdegestrant induced ≥90% degradation of wild-type and mutant ER, inhibited ER-dependent breast cancer cell line proliferation in vitro, and achieved substantial TGI (87%-123%) in MCF7 ...RESULTS: Vepdegestrant induced ≥90% degradation of wild-type and mutant ER, inhibited ER-dependent breast cancer cell line proliferation in vitro, and achieved substantial TGI (87%-123%) in MCF7 orthotopic xenograft models, better than those of the ET agent fulvestrant (31%-80% TGI). In the hormone independent (HI) mutant ER Y537S patient-derived xenograft (PDX) breast cancer model ST941/HI, vepdegestrant achieved tumor regression 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 with fulvestrant, which correlated with improved TGI, suggesting vepdegestrant could be a more effective backbone ET for ...CONCLUSIONS: Vepdegestrant achieved greater ER degradation in vivo compared with fulvestrant, which correlated with improved TGI, suggesting vepdegestrant could be a more effective backbone ET for patients with ER+/HER2- breast cancer. | |||||||||
History |
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-Structure visualization
Supplemental images |
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-Downloads & links
-EMDB archive
Map data | emd_40261.map.gz | 1.3 MB | EMDB map data format | |
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Header (meta data) | emd-40261-v30.xml emd-40261.xml | 22.4 KB 22.4 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_40261_fsc.xml | 7.9 KB | Display | FSC data file |
Images | emd_40261.png | 87.6 KB | ||
Masks | emd_40261_msk_1.map emd_40261_msk_2.map | 52.7 MB 52.7 MB | Mask map | |
Filedesc metadata | emd-40261.cif.gz | 5.3 KB | ||
Others | emd_40261_additional_1.map.gz emd_40261_additional_2.map.gz emd_40261_half_map_1.map.gz emd_40261_half_map_2.map.gz | 49.8 MB 26.7 MB 48.9 MB 48.9 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-40261 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-40261 | HTTPS FTP |
-Validation report
Summary document | emd_40261_validation.pdf.gz | 724.3 KB | Display | EMDB validaton report |
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Full document | emd_40261_full_validation.pdf.gz | 723.9 KB | Display | |
Data in XML | emd_40261_validation.xml.gz | 15.6 KB | Display | |
Data in CIF | emd_40261_validation.cif.gz | 19.7 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-40261 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-40261 | HTTPS FTP |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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-Map
File | Download / File: emd_40261.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||
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Annotation | Map filtered according to local resolution | ||||||||||||||||||||
Voxel size | X=Y=Z: 1.3995 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Mask #1
File | emd_40261_msk_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Mask #2
File | emd_40261_msk_2.map | ||||||||||||
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Density Histograms |
-Additional map: Sharpened map
File | emd_40261_additional_1.map | ||||||||||||
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Annotation | Sharpened map | ||||||||||||
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Density Histograms |
-Additional map: Unsharpened map
File | emd_40261_additional_2.map | ||||||||||||
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Annotation | Unsharpened map | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Half map A
File | emd_40261_half_map_1.map | ||||||||||||
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Annotation | Half map A | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Half map B
File | emd_40261_half_map_2.map | ||||||||||||
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Annotation | Half map B | ||||||||||||
Projections & Slices |
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Density Histograms |
-Sample components
-Entire : Ternary complex of DDB1/CRBN, ARV-471, and the ER ligand-binding ...
Entire | Name: Ternary complex of DDB1/CRBN, ARV-471, and the ER ligand-binding domain |
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Components |
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-Supramolecule #1: Ternary complex of DDB1/CRBN, ARV-471, and the ER ligand-binding ...
Supramolecule | Name: Ternary complex of DDB1/CRBN, ARV-471, and the ER ligand-binding domain type: complex / ID: 1 / Parent: 0 |
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Source (natural) | Organism: Homo sapiens (human) |
-Supramolecule #2: DDB1/CRBN
Supramolecule | Name: DDB1/CRBN / type: complex / ID: 2 / Parent: 1 |
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Source (natural) | Organism: Homo sapiens (human) |
-Supramolecule #3: Estrogen Receptor alpha ligand binding domain
Supramolecule | Name: Estrogen Receptor alpha ligand binding domain / type: complex / ID: 3 / Parent: 1 |
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Source (natural) | Organism: Homo sapiens (human) |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-Sample preparation
Buffer | pH: 7.3 Component:
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Vitrification | Cryogen name: ETHANE / Instrument: SPOTITON / Details: SPT labtech chameleon. |
-Electron microscopy
Microscope | FEI TITAN KRIOS |
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Specialist optics | Energy filter - Name: TFS Selectris X / Energy filter - Slit width: 10 eV |
Details | The 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 recording | Film 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 beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
Electron optics | C2 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 stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |