PXD015412

PXD015412 is an original dataset announced via ProteomeXchange.

Title	Re-evaluation of the mechanism of action of α,β-unsaturated carbonyl DUB inhibitors b-AP15 and VLX1570: CIAPIN1 is a major target of VLX1570 for non-selective covalent modification and aggregation in a multiple myeloma model.
Description	Deubiquitinating enzymes are a growing target class across multiple disease states, with several inhibitors now reported. b-AP15 and VLX1570 are two structurally related USP14/UCH-37 inhibitors. Initially taken forward into a phase I/II clinical trial for refractory Multiple Myeloma, VLX1570 has since been put on full clinical hold due to dose limiting toxicity. Though a proteomic approach, here we demonstrate that these compounds target a diverse range of proteins, resulting in the formation of higher molecular weight complexes. Activity-based proteome profiling identified CIAPIN1 as a sub-micromolar covalent target of VLX1570, and further analysis demonstrated that high molecular weight complex formation leads to aggregation of CIAPIN1 in intact cells.
HostingRepository	PRIDE
AnnounceDate	2020-05-27
AnnouncementXML	Submission_2020-05-27_03:09:53.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Jenny Ward
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2019-09-11 05:42:03	ID requested
⏵ 1	2020-05-27 03:09:54	announced

Ward JA, Pinto-Fernandez A, Cornelissen L, Bonham S, D, í, az-S, á, ez L, Riant O, Huber KVM, Kessler BM, Feron O, Tate EW, -Unsaturated Carbonyl DUB Inhibitors b-AP15 and VLX1570: A Paradigmatic Example of Unspecific Protein Cross-linking with Michael Acceptor Motif-Containing Drugs. J Med Chem, 63(7):3756-3762(2020) [pubmed]

submitter keyword: VLX1570, bAP-15, multiple myeloma, chemoproteomics, proteomics

Edward Tate
contact affiliation	Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, London, UK
contact email	e.tate@imperial.ac.uk
lab head
Jenny Ward
contact affiliation	University of Oxford
contact email	jennifer.ward@ndm.ox.ac.uk
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/2020/05/PXD015412

PRIDE project URI

• PRIDE
  1. PXD015412
     1. Label: PRIDE project
     2. Name: Re-evaluation of the mechanism of action of α,β-unsaturated carbonyl DUB inhibitors b-AP15 and VLX1570: CIAPIN1 is a major target of VLX1570 for non-selective covalent modification and aggregation in a multiple myeloma model.