PXD062227

PXD062227 is an original dataset announced via ProteomeXchange.

Title	Covalent inhibitor design confers activity against both GDP- and GTP-bound forms of KRAS G12C
Description	The discovery of KRAS G12C inactive state inhibitors represents a significant advancement in the field of precision oncology. While inactive state inhibition shows promise in patients, SWII-binding inhibitors targeting both inactive and active states remain an underdeveloped therapeutic modality. Here, we describe the discovery of KRAS G12C dual inhibitors that bind the SWII allosteric site using a chemically differentiated warhead to covalently modify both KRAS G12C inactive and active states. Co-crystal structures reveal that these inhibitors perturb a key water-mediated hydrogen bonding network and trigger allosteric remodeling of the GTP-bound protein surface and Switch I to prevent binding to downstream effectors. Consistent with simultaneous targeting of the active and inactive state, dual inhibitors provide rapid covalent target engagement and suppression of MAPK signaling. However, KRAS G12C dual and inactive state inhibitors demonstrate similar efficacy in cellular and in vivo models despite faster target inhibition afforded by targeting the active state. Furthermore, KRAS G12C dual and inactive state inhibitors show similar cellular efficacy in the presence of growth factors that drive KRAS, wt NRAS and wt HRAS to the active state. These data provide the first detailed account of targeting the active and inactive state of KRAS and highlight the absence of a mechanistic advantage in the context of prolonged KRAS G12C inhibition and efficacy.
HostingRepository	PRIDE
AnnounceDate	2025-11-04
AnnouncementXML	Submission_2025-11-04_08:02:48.106.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Yuka Amako
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2025-03-25 14:27:42	ID requested
⏵ 1	2025-11-04 08:02:48	announced

Dataset with its publication pending

submitter keyword: None

Michelle Stewart
contact affiliation	Bristol Myers Squibb
contact email	Michelle.Stewart@bms.com
lab head
Yuka Amako
contact affiliation	Bristol Myers Squibb
contact email	yuka.amako@bms.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD062227
     1. Label: PRIDE project
     2. Name: Covalent inhibitor design confers activity against both GDP- and GTP-bound forms of KRAS G12C