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- PDB-9hz5: Pre-clinical characterization of novel multi-client inhibitors of... -

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Basic information

Entry
Database: PDB / ID: 9hz5
TitlePre-clinical characterization of novel multi-client inhibitors of Sec61 with broad anti-tumor activity
Components
  • Protein transport protein Sec61 subunit alpha
  • Protein transport protein Sec61 subunit beta
  • Protein transport protein Sec61 subunit gamma
KeywordsPROTEIN TRANSPORT / Sec61 / ribosome / Protein translocation
Function / homology:
Function and homology information
Biological speciesOvis aries (sheep)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.6 Å
AuthorsShahid, R. / Paavilainen, V.O.
Funding support Finland, 2items
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, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 16, 2025Provider: repository / Type: Initial release
Revision 1.1Jul 30, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.journal_volume / _citation.page_last ..._citation.journal_volume / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Protein transport protein Sec61 subunit alpha
A: Protein transport protein Sec61 subunit gamma
C: Protein transport protein Sec61 subunit beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)55,6334
Polymers54,8683
Non-polymers7651
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 Protein transport protein Sec61 subunit alpha


Mass: 45829.012 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Ovis aries (sheep)
#2: Protein Protein transport protein Sec61 subunit gamma


Mass: 6722.062 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Ovis aries (sheep)
#3: Protein/peptide Protein transport protein Sec61 subunit beta


Mass: 2316.929 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Ovis aries (sheep)
#4: Chemical ChemComp-A1A2B / 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


Mass: 765.057 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C38H61FN6O5S2
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: Sec61 translocon complex with small molecule / Type: COMPLEX / Entity ID: #1-#3 / Source: NATURAL
Molecular weightValue: 3 MDa / Experimental value: NO
Source (natural)Organism: Ovis aries (sheep)
Buffer solutionpH: 7.4
SpecimenConc.: 0.1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER
VitrificationCryogen name: ETHANE

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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: 2000 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 47 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1163355
3D reconstructionResolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1564411 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT

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