PXD071555

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

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PRIDE project URI

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