PXD015207-1

PXD015207 is an original dataset announced via ProteomeXchange.

Title	Discovery of a Small Molecule Degrader that Sustains pan-AKT Degradation and Downstream Signaling Effects
Description	The PI3K/AKT signaling cascade is one of the most commonly dysregulated pathways in cancer, with over 50% of tumors showing aberrant AKT hyperactivation. Although potent small molecule AKT inhibitors have entered clinical trials, robust and durable therapeutic responses have not been observed. As an alternative strategy to target AKT, we report the development of INY-03-041, a pan-AKT degrader consisting of GDC-0068, an AKT inhibitor, conjugated to lenalidomide, a recruiter of the E3 ubiquitin ligase, Cereblon (CRBN). INY-03-041 induced potent degradation of all three AKT isoforms and displayed enhanced anti-proliferative effects relative to GDC-0068. Notably, INY-03-041 promoted sustained AKT degradation and inhibition of downstream signaling effects for up to 96 hours, even after compound washout. Overall, our findings suggest that AKT degradation may provide prolonged pharmacological effects compared to inhibition, and highlight the potential advantages of AKT-targeted degradation.
HostingRepository	PRIDE
AnnounceDate	2019-11-27
AnnouncementXML	Submission_2019-11-27_03:54:14.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: 9606;
ModificationList	phosphorylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2019-08-29 03:36:30	ID requested
⏵ 1	2019-11-27 03:54:15	announced

Dataset with its publication pending

submitter keyword: AKT, serine/threonine kinase, cancer PROTAC, CRBN, ubiquitin, crl4

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

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PRIDE project URI

• PRIDE
  1. PXD015207
     1. Label: PRIDE project
     2. Name: Discovery of a Small Molecule Degrader that Sustains pan-AKT Degradation and Downstream Signaling Effects