PXD025898

PXD025898 is an original dataset announced via ProteomeXchange.

Title	NMS-873 leads to dysfunctional glycometabolism in a p97-independent manner
Description	ATP-competitive p97 inhibitor CB-5339, the successor of CB-5083, is being evaluated in Phase 1 clinical trials for anti-cancer therapy. Different modes of action p97 inhibitors such as allosteric inhibitors are useful to overcome one the major problems of targeted therapy: drug-induced resistance. We previously demonstrated allosteric p97 inhibitor NMS-873 can overcome CB-5083-induced resistance. Here, we found that NMS-873 but not CB-5083 affected glycometabolism. By establishing NMS-873-resistant cell lines and performing both cell-based and proteomic analysis, we confirmed that NMS-873 dysregulates glycometabolism in a p97-independent manner. We then used proteome integral solubility alteration with a temperature-based method (PISA T) to identify NDUFAF5 as one of the potential targets of NMS-873 in the mitochondrial complex I. Overall, we employed chemical proteomics and drug-induced thermal proteome changes to identify drug targets, in combination with drug-resistant cell lines to dissect on- and off-target effects. We also demonstrated that glycolysis inhibitor 2-DG enhanced the anti-proliferative effect of NMS-873. The polypharmacology of NMS-873 can be advantageous for anti-cancer therapy.
HostingRepository	PRIDE
AnnounceDate	2022-05-19
AnnouncementXML	Submission_2022-05-19_07:32:37.679.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD025898
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Shan Li
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2021-05-09 07:51:03	ID requested
⏵ 1	2022-05-19 07:32:38	announced

Li S, Wang F, Zhang G, Chou TF, NMS-873 Leads to Dysfunctional Glycometabolism in A p97-Independent Manner in HCT116 Colon Cancer Cells. Pharmaceutics, 14(4):(2022) [pubmed]

ProteomeXchange project tag: Cancer (B/D-HPP), Biology/Disease-Driven Human Proteome Project (B/D-HPP), Human Proteome Project

submitter keyword: p97 inhibitor, glycometabolism, resistance, protein stability, proteomics

Tsui-Fen Chou
contact affiliation	BBE, Caltech
contact email	tfchou@caltech.edu
lab head
Shan Li
contact affiliation	Caltech
contact email	lflshan@caltech.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD025898
     1. Label: PRIDE project
     2. Name: NMS-873 leads to dysfunctional glycometabolism in a p97-independent manner