PXD013779-1

PXD013779 is an original dataset announced via ProteomeXchange.

Title	Characterization of SGK3-PROTAC1, a highly specific SGK3 kinase PROTAC degrader
Description	SGK3 is a PX domain containing protein kinase activated at endosomes downstream of Class 1 and 3 PI3K family members by growth factors and oncogenic mutations. SGK3 plays a key role in mediating resistance of breast cancer to Class 1 PI3K or Akt inhibitors, by substituting for loss of Akt and restoring proliferative pathways such as mTORC1 signaling. Here we describe the development of SGK3-PROTAC1, a Proteolysis Targeting Chimera (PROTAC) compound formed by the fusion of the 308-R SGK3 inhibitor with the VH032 VHL binding ligand via a 13-atom linker. In HEK293 cells, 0.3 µM SGK3-PROTAC1 induced 50% degradation of endogenous SGK3 within 2 hours, with maximal 85% degradation observed within 8 hours, accompanied by a loss of phosphorylation of NDRG1, an SGK3 substrate. SGK3-PROTAC1 did not degrade closely related SGK1 and SGK2 isoforms and proteomic analysis in HEK293 cells revealed that SGK3 was the only cellular protein whose cellular levels was significantly reduced following treatment with SGK3-PROTAC1. Low doses of SGK3-PROTAC1 (0.1-0.3 µM) restored sensitivity of SGK3 dependent ZR-75-1 and CAMA-1 breast cancer cells to Akt (AZD5363) and PI3K (GDC0941) inhibitors, under conditions which an epimer analogue incapable of binding to the VHL E3 ligase had no impact. SGK3-PROTAC1 suppressed proliferation of ZR-75-1 and CAMA-1 cancer cell lines treated with a PI3K inhibitor (GDC0941) more effectively than could be achieved by a conventional SGK isoform inhibitor (14H). This work provides a further example of the benefit of the PROTAC approach in targeting protein kinase signaling pathways with greater efficacy and selectivity than can be achieved with conventional inhibitors. SGK3-PROTAC1 will be an important reagent to explore the roles of the SGK3 pathway.
HostingRepository	PRIDE
AnnounceDate	2019-11-12
AnnouncementXML	Submission_2019-11-11_18:26:24.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Houjiang Zhou
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2019-05-09 01:46:49	ID requested
⏵ 1	2019-11-11 18:26:25	announced
2	2024-10-22 04:15:05	announced	2024-10-22: Updated project metadata.

Tovell H, Testa A, Zhou H, Shpiro N, Crafter C, Ciulli A, Alessi DR, Design and Characterization of SGK3-PROTAC1, an Isoform Specific SGK3 Kinase PROTAC Degrader. ACS Chem Biol, 14(9):2024-2034(2019) [pubmed]

submitter keyword: PROTAC, SGK3, Degradation

Houjiang Zhou
contact affiliation	Medical Research Council (MRC) Protein Phosphorylation andUbiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK
contact email	h.y.zhou@dundee.ac.uk
lab head
Houjiang Zhou
contact affiliation	University of Dundee
contact email	h.y.zhou@dundee.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD013779
     1. Label: PRIDE project
     2. Name: Characterization of SGK3-PROTAC1, a highly specific SGK3 kinase PROTAC degrader