9TFF

KIT kinase domain in complex with a pyrrolopyrimidine-based compound (17)

This is a non-PDB format compatible entry.

Summary for 9TFF

• Entry DOI: 10.2210/pdb9tff/pdb
• Descriptor: Mast/stem cell growth factor receptor Kit, 4-[4-[5-(phenylmethyl)pyrimidin-2-yl]piperazin-1-yl]-7~{H}-pyrrolo[2,3-d]pyrimidine (3 entities in total)
• Functional Keywords: kit protein kinase, inhibitor, tyrosine kinase, transmembrane receptor, stem cell factor, scf, stem cell factor receptor, gist, gastrointestinal stromal tumors, p10721, transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 75131.74

Authors

Scrima, A.,Mueller, M.P.,Rauh, D. (deposition date: 2025-11-27, release date: 2026-07-15, Last modification date: 2026-08-19)

Primary citation

Schulz, T.,Beerbaum, M.,Scrima, A.,Jantzen, H.,Teuber, A.,Muhlenberg, T.,Ebel, L.,Garcia-Fossa, F.,George, A.,Berner, N.,Weisner, J.,Muller, M.P.,Wilhelm, S.,Sievers, S.,Bauer, S.,Rauh, D.
Structure-based scaffold hopping reveals strategies to overcome oncogenic KIT and PDGFRA mutation-driven drug-resistance in GIST.
Nat Commun, 17:-, 2026

PubMed Abstract: 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 kinase inhibitors with selectivity for mutant KIT/PDGFRA. Using structure-activity relationship (SAR) studies and 14 determined co-crystal structures, including a structure of the PDGFRA-G680R solvent-front mutation, we define key molecular interactions underlying resistance and inhibitor selectivity. Our lead 6,7-quinazoline-based 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 shows the molecular basis for targeting solvent-front mutations across oncogenic kinases.

PubMed: 42562826
DOI: 10.1038/s41467-026-76340-7

Experimental method

X-RAY DIFFRACTION (1.8 Å)