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- EMDB-52520: Pre-clinical characterization of novel multi-client inhibitors of... -

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Basic information

Entry
Database: EMDB / ID: EMD-52520
TitlePre-clinical characterization of novel multi-client inhibitors of Sec61 with broad anti-tumor activity
Map data
Sample
  • Complex: Sec61 translocon complex with small molecule
    • Protein or peptide: Protein transport protein Sec61 subunit alpha
    • Protein or peptide: Protein transport protein Sec61 subunit gamma
    • Protein or peptide: Protein transport protein Sec61 subunit beta
  • Ligand: 4-{(3S)-9-(cyclohexylmethyl)-5-[(3R,5R)-4-(3-fluoro-5-methoxyphenyl)-3,5-dimethylpiperazine-1-sulfonyl]-3-methyl-1,5,9-triazacyclododecane-1-sulfonyl}-N,N-dimethylaniline
KeywordsSec61 / ribosome / Protein translocation / PROTEIN TRANSPORT
Biological speciesOvis aries (sheep)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.6 Å
AuthorsShahid R / Paavilainen VO
Funding support Finland, 2 items
OrganizationGrant numberCountry
Academy of Finland338836 Finland
Jane and Aatos Erkko Foundation Finland
CitationJournal: J Pharmacol Exp Ther / Year: 2025
Title: Preclinical characterization of novel multi-client inhibitors of Sec61 with broad antitumor activity.
Authors: Eric Lowe / Janet L Anderl / David Bade / Cristina Delgado-Martin / Chengguo Dong / R Andrea Fan / Ying Fang / Jing Jiang / Henry W B Johnson / Aaron Kempema / Phil McGilvray / Dustin McMinn ...Authors: Eric Lowe / Janet L Anderl / David Bade / Cristina Delgado-Martin / Chengguo Dong / R Andrea Fan / Ying Fang / Jing Jiang / Henry W B Johnson / Aaron Kempema / Phil McGilvray / Dustin McMinn / Beatriz Millare / Tony Muchamuel / Nicole Poweleit / Yu Qian / Shahid Rehan / Giovanna Scapin / Ajia Sugahara / Dale Tranter / Brian Tuch / Jinhai Wang / Laurie Wang / Jennifer A Whang / Patricia Zuno-Mitchell / Ville O Paavilainen / Eunyong Park / Jack Taunton / Christopher J Kirk / Neel K Anand /
Abstract: The Sec61 translocon mediates entry of most secreted and transmembrane proteins into the endoplasmic reticulum, providing a novel therapeutic target to block the expression of protumorigenic factors. ...The Sec61 translocon mediates entry of most secreted and transmembrane proteins into the endoplasmic reticulum, providing a novel therapeutic target to block the expression of protumorigenic factors. Sec61 inhibitors with antitumor activity, mostly derived from natural products, have been reported. However, poor tolerability and suboptimal pharmaceutical properties have precluded their further development. We report here the discovery and characterization of KZR-834 and KZR-261, related small molecule analogs that directly bind to the Sec61 channel to potently inhibit the biogenesis of a subset of Sec61 client proteins. This client inhibition profile includes several tumorigenic factors, results in the activation of an endoplasmic reticulum stress response, and leads to broad anticancer effects in vitro. In vivo, KZR-261 was well tolerated and exhibits antitumor effects across multiple models, both as a single agent and in combination with anti-PD-1 immunotherapy. Based on the strength of this preclinical data, KZR-261 progressed into a phase I clinical trial (NCT05047536) in patients with malignant disease, where it was found to be well tolerated at doses that achieved durable stable disease. These results highlight the potential of Sec61 inhibition as a novel therapeutic target. SIGNIFICANCE STATEMENT: KZR-834 and KZR-261 are novel Sec61 inhibitors with the ability to block multiple Sec61 client proteins, leading to well-tolerated efficacy in in vivo cancer models. This represents a novel mechanism for blocking expression of oncogenic factors, including those not amenable to targeting through conventional methods.
History
DepositionJan 13, 2025-
Header (metadata) releaseJul 16, 2025-
Map releaseJul 16, 2025-
UpdateJul 30, 2025-
Current statusJul 30, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_52520.png

Downloads & links

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Map

FileDownload / File: emd_52520.map.gz / Format: CCP4 / Size: 824 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 600 pix.
= 498. Å		0.83 Å/pix.
x 600 pix.
= 498. Å		0.83 Å/pix.
x 600 pix.
= 498. Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.00001
Minimum - Maximum-0.39745665 - 1.2370273
Average (Standard dev.)0.0012252385 (±0.011247104)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions600600600
Spacing600600600
CellA=B=C: 498.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_52520_half_map_1.map
Projections & Slices
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Half map: #2

Fileemd_52520_half_map_2.map
Projections & Slices
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Sample components

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Entire : Sec61 translocon complex with small molecule

EntireName: Sec61 translocon complex with small molecule
Components
  • Complex: Sec61 translocon complex with small molecule
    • Protein or peptide: Protein transport protein Sec61 subunit alpha
    • Protein or peptide: Protein transport protein Sec61 subunit gamma
    • Protein or peptide: Protein transport protein Sec61 subunit beta
  • Ligand: 4-{(3S)-9-(cyclohexylmethyl)-5-[(3R,5R)-4-(3-fluoro-5-methoxyphenyl)-3,5-dimethylpiperazine-1-sulfonyl]-3-methyl-1,5,9-triazacyclododecane-1-sulfonyl}-N,N-dimethylaniline

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Supramolecule #1: Sec61 translocon complex with small molecule

SupramoleculeName: Sec61 translocon complex with small molecule / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Ovis aries (sheep)
Molecular weightTheoretical: 3 MDa

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Macromolecule #1: Protein transport protein Sec61 subunit alpha

MacromoleculeName: Protein transport protein Sec61 subunit alpha / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Ovis aries (sheep)
Molecular weightTheoretical: 45.829012 KDa
SequenceString: EIQKPERKIQ FKEKVLWTAI TLFIFLVCCQ IPLFGIMSSD SADPFYWMRV ILASNRGTLM ELGISPIVTS GLIMQLLAGA KKDRALFNG AQKLFGMIIT IGQSIVYVMT MGAGICLLIT IQLFVAGLIV LLLDELLQKG YGISLFIATN ICETIVWKAF S PTTVNTGR ...String:
EIQKPERKIQ FKEKVLWTAI TLFIFLVCCQ IPLFGIMSSD SADPFYWMRV ILASNRGTLM ELGISPIVTS GLIMQLLAGA KKDRALFNG AQKLFGMIIT IGQSIVYVMT MGAGICLLIT IQLFVAGLIV LLLDELLQKG YGISLFIATN ICETIVWKAF S PTTVNTGR GMEFEGAIIA LFHLLATRTD KVRALREAFY RQNLPNLMNL IATIFVFAVV IYFQGFRVDL PIKSARYRGQ YN TYPIKLF YTSNIPIILQ SALVSNLYVI SQMLSARFSG NLLVSLLGTW LCYYLSPPES FGSVLEDPVH AVVYIVFMLG SCA FFSKTW IEVSGSSAKD VAKQLKEQQM VMRGHRETSM VHELNRYIPT AAAFGGLCIG ALSVLADFLG AIGSGTGILL AVTI IYQYF EIFVKEQ

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Macromolecule #2: Protein transport protein Sec61 subunit gamma

MacromoleculeName: Protein transport protein Sec61 subunit gamma / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Ovis aries (sheep)
Molecular weightTheoretical: 6.722062 KDa
SequenceString:
AAFVEPSRQF VKDSIRLVKR CTKPDRKEFQ KIAMATAIGF AIMGFIGFFV KLIHIPINN

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Macromolecule #3: Protein transport protein Sec61 subunit beta

MacromoleculeName: Protein transport protein Sec61 subunit beta / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Ovis aries (sheep)
Molecular weightTheoretical: 2.316929 KDa
SequenceString:
VPVLVMSLLF IASVFMLHIW

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Macromolecule #4: 4-{(3S)-9-(cyclohexylmethyl)-5-[(3R,5R)-4-(3-fluoro-5-methoxyphen...

MacromoleculeName: 4-{(3S)-9-(cyclohexylmethyl)-5-[(3R,5R)-4-(3-fluoro-5-methoxyphenyl)-3,5-dimethylpiperazine-1-sulfonyl]-3-methyl-1,5,9-triazacyclododecane-1-sulfonyl}-N,N-dimethylaniline
type: ligand / ID: 4 / Number of copies: 1 / Formula: A1A2B
Molecular weightTheoretical: 765.057 Da

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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

Concentration0.1 mg/mL
BufferpH: 7.4
GridMaterial: COPPER
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 47.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1163355
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7zl3

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 1564411
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: ANGULAR RECONSTITUTION

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Atomic model buiding 1

RefinementProtocol: RIGID BODY FIT
Output model

PDB-9hz5:
Pre-clinical characterization of novel multi-client inhibitors of Sec61 with broad anti-tumor activity

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