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PXD061282

PXD061282 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitlePROTAC-mediated degradation of TAF1 induces apoptosis in AML cells and inhibits tumor growth in vivo
DescriptionThe bromodomain-containing protein, TAF1 (TFII-250), is the largest component of the multiprotein assembly TFIID, a dynamic complex that serves as a general factor for transcription initiation. CRISPR and RNAi screens of pan cancer cell lines revealed TAF1 is broadly required for optimal cell growth and survival, but a subset of cell lines showed enhanced TAF1 dependence. These observations suggest that TAF1 has the potential to serve as a therapeutic target in sensitive tumors. Current approaches employed to target TAF1 are limited to monovalent small molecule inhibitors of the bromodomain. However, recent studies showed that such inhibitors lack cancer cell kill potential. We applied a structure-guided approach to generate cereblon (CRBN) recruiting PROTAC degraders of TAF1 using the chemical scaffolds of ceralasertib and GNE371. We present evidence that GNE371-based PROTACs are effective in degradation of TAF1 at concentrations as low as 1 nM. TAF1 depletion activated p53 and induced apoptosis in AML cell lines and certain solid tumor cells. An in vivo active TAF1 PROTAC inhibited the growth of AML tumor xenograft. The results showed that inhibition of bromodomain is not sufficient to inactivate TAF1 functions, while a PROTAC approach induces strong biological effects. Furthermore, TAF1 PROTACs have therapeutic potential against AML and other sensitive tumors.
HostingRepositoryPRIDE
AnnounceDate2025-02-28
AnnouncementXMLSubmission_2025-02-28_12:00:09.865.xml
DigitalObjectIdentifierhttps://dx.doi.org/10.6019/PXD061282
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportSupported dataset by repository
PrimarySubmitterJohn Koomen
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListmonohydroxylated residue; iodoacetamide derivatized residue
InstrumentOrbitrap Exploris 480
Dataset History
RevisionDatetimeStatusChangeLog Entry
02025-02-27 12:51:03ID requested
12025-02-28 12:00:10announced
Publication List
10.6019/PXD061282;
Keyword List
submitter keyword: TAF1, Apoptosis,Protein Targeting Chimera, Acute Myeloid Leukemia
Contact List
Jiandong Chen
contact affiliationMolecular Oncology Moffitt Cancer Center Tampa, FL, USA
contact emailjiandong.chen@moffitt.org
lab head
John Koomen
contact affiliationMoffitt Cancer Center
contact emailjohn.koomen@moffitt.org
dataset submitter
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Dataset FTP location
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