PXD071555-1

PXD071555 is an original dataset announced via ProteomeXchange.

Title	Chemoproteomic Profiling of VVD-065 Selectivity
Description	The NRF2 transcription factor is constitutively active in cancer where it functions to maintain oxidative homeostasis and reprogram cellular metabolism. NRF2-active tumors exhibit NRF2-dependency and resistance to chemo/radiotherapy. Here we characterize VVD-065, a first-in-class NRF2 inhibitor that acts via an unprecedented allosteric molecular glue mechanism. In the absence of stress or mutation, NRF2 is rapidly degraded by the KEAP1-CUL3 ubiquitin-ligase complex. VVD-065 specifically and covalently engages Cys151 on KEAP1, which in turn promotes KEAP1-CUL3 complex formation, leading to enhancement of NRF2 degradation. Previously reported Cys151-directed compounds decrease KEAP1-CUL3 interactions and stabilize NRF2, thus establishing KEAP1_Cys151 as a tunable regulator of the KEAP1-CUL3 9 complex and NRF2 stability. VVD-065 inhibited NRF2-dependent tumor growth and sensitized cancers to 10 chemo/radiotherapy, supporting an open Phase I clinical trial (NCT05954312).
HostingRepository	PRIDE
AnnounceDate	2025-12-10
AnnouncementXML	Submission_2025-12-10_13:38:16.187.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Christie Eissler
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2025-12-03 19:22:27	ID requested
⏵ 1	2025-12-10 13:38:16	announced

Dataset with its publication pending

submitter keyword: NRF2, KEAP1, VVD-065

Gabe Simon
contact affiliation	Vividion Therapeutics
contact email	gabe@vividion.com
lab head
Christie Eissler
contact affiliation	Vividion Therapeutics
contact email	christiee@vividion.com
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/12/PXD071555

PRIDE project URI

• PRIDE
  1. PXD071555
     1. Label: PRIDE project
     2. Name: Chemoproteomic Profiling of VVD-065 Selectivity