PXD061282

PXD061282 is an original dataset announced via ProteomeXchange.

Title	PROTAC-mediated degradation of TAF1 induces apoptosis in AML cells and inhibits tumor growth in vivo
Description	The 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.
HostingRepository	PRIDE
AnnounceDate	2025-02-28
AnnouncementXML	Submission_2025-02-28_12:00:09.865.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD061282
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	John Koomen
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2025-02-27 12:51:03	ID requested
⏵ 1	2025-02-28 12:00:10	announced

10.6019/PXD061282;

submitter keyword: TAF1, Apoptosis,Protein Targeting Chimera, Acute Myeloid Leukemia

Jiandong Chen
contact affiliation	Molecular Oncology Moffitt Cancer Center Tampa, FL, USA
contact email	jiandong.chen@moffitt.org
lab head
John Koomen
contact affiliation	Moffitt Cancer Center
contact email	john.koomen@moffitt.org
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD061282
     1. Label: PRIDE project
     2. Name: PROTAC-mediated degradation of TAF1 induces apoptosis in AML cells and inhibits tumor growth in vivo