PXD065163-1

PXD065163 is an original dataset announced via ProteomeXchange.

Title	Identification of a Highly Cooperative PROTAC Degrader Targeting GTP-loaded KRAS(on) Alleles
Description	Kirsten rat sarcoma viral oncogene homolog (KRAS) is a frequently mutated oncogene in multiple types of cancer and is a high priority target for oncology drug development. There are many different KRAS mutations, including mutations which favour the GTP-loaded ‘active’ state of KRAS, (KRAS(on)), that can lead to tumorigenesis. However, small molecule interventions thus far have predominantly targeted single mutations of ‘inactive’ GDP-loaded KRAS, (KRAS(off)), such as KRASG12C. Here, we address this gap through the development of heterobifunctional VHL-based PROTACs capable of engaging and degrading KRAS(on), thus addressing a wider range of KRAS mutations. By studying ternary complex affinity, stability and binding modes using SPR binding assays and X-ray cocrystal structures we identified PROTACs that exhibit the ability to cooperatively and stably bind GCP-loaded KRAS as representative of KRAS(on) variants. Degrader activity profiling in relevant cancer cells supported the discovery of ACBI4, a PROTAC which forms a highly stable ternary complex between VHL and GTP-bound KRAS and which potently degrades KRASG12R, leading to anti-proliferative effect. ACBI4 provides a new chemical tool for studying the impact of degrading KRAS(on) mutants which is not possible with current pan-KRAS inhibitors or degraders.
HostingRepository	PRIDE
AnnounceDate	2025-11-24
AnnouncementXML	Submission_2025-11-23_16:47:50.231.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Gajanan Sathe
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2025-06-18 08:53:18	ID requested
⏵ 1	2025-11-23 16:47:51	announced

10.1021/jacs.5c10354;

Vetma V, Puoti I, Karolak NK, Chakraborti S, Diers E, Girardi E, Khan S, Kidd G, Kropatsch KG, Mclennan R, O'Connor S, Samwer M, Trainor N, Whitworth C, Wijaya AJ, Wong JYF, Zollman D, Farnaby W, Popow J, Ciulli A, Ettmayer P, McAulay K, Identification of a Highly Cooperative PROTAC Degrader Targeting GTP-Loaded KRAS(On) Alleles. J Am Chem Soc, 147(45):41367-41378(2025) [pubmed]

submitter keyword: targeted protein degradation,KRAS, PROTAC, cooperativity

Kirsten McAulay
contact affiliation	Centre for Targeted Protein Degradation (CeTPD) University of Dundee
contact email	kmcaulay001@dundee.ac.uk
lab head
Gajanan Sathe
contact affiliation	Centre for Targeted Protein Degradation (CeTPD) University of Dundee
contact email	gsathe001@dundee.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD065163
     1. Label: PRIDE project
     2. Name: Identification of a Highly Cooperative PROTAC Degrader Targeting GTP-loaded KRAS(on) Alleles