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PXD036191-2

PXD036191 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleDiscovery of a small molecule inhibitor of the UBE2F-CRL5 axis that induces apoptosis and G2/M arrest and confers radiosensitization
DescriptionProtein 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.
HostingRepositoryPRIDE
AnnounceDate2023-11-14
AnnouncementXMLSubmission_2023-11-14_08:58:04.127.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterTiantian Xu
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListNo PTMs are included in the dataset
InstrumenttimsTOF Pro
Dataset History
RevisionDatetimeStatusChangeLog Entry
02022-08-21 03:57:05ID requested
12022-10-18 18:11:05announced
22023-11-14 08:58:04announced2023-11-14: Updated project metadata.
Publication List
Dataset with its publication pending
Keyword List
submitter keyword: UBE2F
Neddylation
Apoptosis
Cell cycle arrest
Small molecule inhibitor
Contact List
Yi Sun
contact affiliation1Cancer 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 emailyisun@zju.edu.cn
lab head
Tiantian Xu
contact affiliationInstitute of Translational Medicine, Zhejiang University School of Medicine
contact emailtiantianxu@zju.edu.cn
dataset submitter
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Dataset FTP location
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