PXD036191

PXD036191 is an original dataset announced via ProteomeXchange.

Title	Discovery of a small molecule inhibitor of the UBE2F-CRL5 axis that induces apoptosis and G2/M arrest and confers radiosensitization
Description	Protein neddylation modification is catalyzed by a neddylation activating enzyme (NAE, E1), an E2 conjugating enzyme and an E3 ligase. In various types of human cancers, the neddylation pathway was abnormally activated. Our previous study validated that neddylation E2 UBE2F is a promising lung cancer target. However, although NAE inhibitor MLN4924/pevonedistat is currently in few clinical trials for anticancer application, no small molecule was reported that targets UBE2F. Here, we report, for the first time, the discovery, via structure-based virtual screen and chemical optimization, of such a small molecule, designated as HA-9104. HA-9104 binds to UBE2F, reduces its protein levels, and consequently inhibits cullin-5 neddylation to inactivate CRL5 (cullin-RING ligase-5) ligase, leading to accumulation of CRL5 substrate, NOXA, to induce apoptosis. Moreover, HA-9104 appears to form the DNA adduct via its 7-azaindole group to induce DNA damage and G2/M arrest. Biologically, HA-9104 effectively suppresses the growth and survival of lung cancer cells and confers radiosensitization in both in vitro cell culture and in vivo xenograft tumor models. Taken together, our study discovered a small molecule HA-9104 that targets the UBE2F-CRL5 axis with anticancer activity alone or in combination with radiation.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:58:04.127.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Tiantian Xu
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2022-08-21 03:57:05	ID requested
1	2022-10-18 18:11:05	announced
⏵ 2	2023-11-14 08:58:04	announced	2023-11-14: Updated project metadata.

Dataset with its publication pending

submitter keyword: UBE2F

Neddylation

Apoptosis

Cell cycle arrest

Small molecule inhibitor

Yi Sun
contact affiliation	1Cancer Institute, the Second Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, China 2Cancer Center, Zhejiang University, Hangzhou 310058, China 3Research Center for Life Science and Human Health, Binjiang Institute of Zhejiang University, Hangzhou 310053, China
contact email	yisun@zju.edu.cn
lab head
Tiantian Xu
contact affiliation	Institute of Translational Medicine, Zhejiang University School of Medicine
contact email	tiantianxu@zju.edu.cn
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/2022/10/PXD036191

PRIDE project URI

• PRIDE
  1. PXD036191
     1. Label: PRIDE project
     2. Name: Discovery of a small molecule inhibitor of the UBE2F-CRL5 axis that induces apoptosis and G2/M arrest and confers radiosensitization