PXD077574-1

PXD077574 is an original dataset announced via ProteomeXchange.

Title	Structure-based Scaffold Hopping Reveals Strategies to Overcome Oncogenic KIT and PDGFRA Mutation-Driven Drug-Resistance in GIST
Description	Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Current tyrosine kinase inhibitors (TKIs) targeting oncogenic KIT and PDGFRA have improved patient outcomes, yet off-target toxicities and drug resistance mutations remain major clinical challenges. Many approved TKIs, often repurposed from other cancer indications, harbor diverse hinge-binding motifs that limit activity against resistance mutations clustering in the ATP-binding pocket of the kinase domain. Here, we describe a structure-based scaffold-hopping strategy to design novel inhibitors with selectivity for mutant KIT/PDGFRA. Using structure-activity relationship (SAR) studies and 14 newly determined co-crystal structures, including the first structure of the PDGFRA-G680R solvent-front mutation, we define key molecular interactions underlying resistance and inhibitor selectivity. Our lead 6,7-quinazolinebased inhibitors show high potency against clinically relevant KIT/PDGFRA mutations and effectively suppress downstream signaling. These compounds provide selective chemical tools to interrogate resistance mechanisms, and the PDGFRA-G680R structure offers new insights for targeting solvent-front mutations across oncogenic kinases.
HostingRepository	PRIDE
AnnounceDate	2026-08-03
AnnouncementXML	Submission_2026-08-03_07:59:28.721.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Nicola Berner
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Astral

Revision	Datetime	Status	ChangeLog Entry
0	2026-04-24 03:04:18	ID requested
⏵ 1	2026-08-03 07:59:29	announced

10.1038/S41467-026-76340-7;

submitter keyword: selectivity profiling, GIST, PDGFRA, KIT, Drug resistance,Kinobeads

Bernhard Kuster
contact affiliation	School of Life Sciences, Technical University of Munich, Freising, Germany
contact email	kuster@tum.de
lab head
Nicola Berner
contact affiliation	German Cancer Consortium (DKTK), Germany Chair of Proteomics and Bioanalytics Technical University of Munich (TUM), Freising, Germany German Cancer Research Center (DKFZ), Heidelberg, Germany
contact email	n.berner@tum.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD077574
     1. Label: PRIDE project
     2. Name: Structure-based Scaffold Hopping Reveals Strategies to Overcome Oncogenic KIT and PDGFRA Mutation-Driven Drug-Resistance in GIST