PXD014646

PXD014646 is an original dataset announced via ProteomeXchange.

Title	Exploring targeted degradation strategy for oncogenic KRASG12C
Description	KRAS is the most frequently mutated oncogene found in pancreatic, colorectal, and lung cancers. Although it has been challenging to identify targeted therapies for cancers harboring KRAS mutations, one particular form of mutant KRAS, namely KRASG12C, can be targeted by small molecule inhibitors that form covalent bonds with cysteine 12 (C12). Here, we designed a library of C12-directed covalent degrader molecules (PROTACs) and subjected them to a rigorous evaluation process to rapidly identify a lead compound. Although our lead degrader successfully engaged CRBN in cells, bound KRASG12C in vitro, induced CRBN/ KRASG12C dimerization, and degraded GFP-KRASG12C in GFP reporter cells in a CRBN-dependent manner, it failed to degrade endogenous KRASG12C in pancreatic and lung cancer cells. Our data suggest that inability of the lead degrader to effectively polyubiquitinate endogenous KRASG12C underlies the lack of activity. We discuss challenges for achieving targeted KRASG12C degradation and propose several possible solutions which may lead to efficient degradation of endogenous KRASG12C.
HostingRepository	PRIDE
AnnounceDate	2020-01-09
AnnouncementXML	Submission_2020-01-09_00:47:46.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	TMT6plex-126 reporter+balance reagent acylated residue; phosphorylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2019-07-17 04:06:53	ID requested
⏵ 1	2020-01-09 00:58:22	announced

Zeng M, Xiong Y, Safaee N, Nowak RP, Donovan KA, Yuan CJ, Nabet B, Gero TW, Feru F, Li L, Gondi S, Ombelets LJ, Quan C, J, ä, nne PA, Kostic M, Scott DA, Westover KD, Fischer ES, Gray NS, . Cell Chem Biol, 27(1):19-31.e6(2020) [pubmed]

submitter keyword: KRAS, oncogene, 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

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/2020/01/PXD014646

PRIDE project URI

• PRIDE
  1. PXD014646
     1. Label: PRIDE project
     2. Name: Exploring targeted degradation strategy for oncogenic KRASG12C