PXD072361

PXD072361 is an original dataset announced via ProteomeXchange.

Title	Degron-independent recruitment of KAT2A redefines the breadth of CRBN-based molecular-glue targets
Description	Lysine acetyltransferases (KATs) frequently cooperate with oncogenes such as c-Myc, estrogen receptor, and KMT2A-fusions to sustain malignant programs. Therapeutic targeting of KAT proteins has shown clinical efficacy, yet achieving homolog-selectivity for most KATs remains a major challenge. Here, by extending CRBN-based molecular glues beyond the canonical degron space, we develop a degrader of KAT2A exhibiting biochemical selectivity over all members of the KAT family. Cryo-EM structures reveal that CRBN engages KAT2A independent of a degron; instead, the molecular glue engages a surface-exposed tyrosine, mimicking antibody-like molecular recognition. Optimized molecular glues demonstrate that selective KAT2A degradation leads to potent ablation of H3K9Ac, antiproliferative effects in AML cell lines, and in vivo efficacy in a patient-derived xenograft model. Overall, these findings establish KAT2A as a targetable vulnerability, laying the foundation for the development of KAT2A-degrading molecular glues to treat a wide range of malignancies. More generally, the unanticipated binding mode suggests that CRBN-based molecular glues may be limited only by the accessible chemical diversity.
HostingRepository	PRIDE
AnnounceDate	2026-08-29
AnnouncementXML	Submission_2026-08-29_13:29:50.314.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Eric Fischer
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	iodoacetamide derivatized residue
Instrument	timsTOF Pro 2

Revision	Datetime	Status	ChangeLog Entry
0	2025-12-23 12:14:34	ID requested
⏵ 1	2026-08-29 13:29:51	announced

10.1126/science.aef5391;

Ojeda S, Wang M, Baek K, Bourgeois W, Sommerschield A, Yue H, Metivier RJ, Karagiannis P, Levitz TS, Xiong Y, Donovan KA, Armstrong SA, Fischer ES, Degron-independent recruitment of KAT2A expands the target space of CRBN molecular glues. Science, 393(6807):188-194(2026) [pubmed]

submitter keyword: None

Eric Fischer
contact affiliation	Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
contact email	eric_fischer@dfci.harvard.edu
lab head
Eric Fischer
contact affiliation	Dana-Farber Cancer Institute
contact email	eric_fischer@dfci.harvard.edu
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/2026/08/PXD072361

PRIDE project URI

• PRIDE
  1. PXD072361
     1. Label: PRIDE project
     2. Name: Degron-independent recruitment of KAT2A redefines the breadth of CRBN-based molecular-glue targets