9TF9
PDGFRA-G680R mutant kinase domain in complex with avapritinib
Summary for 9TF9
| Entry DOI | 10.2210/pdb9tf9/pdb |
| Descriptor | Platelet-derived growth factor receptor alpha, Avapritinib (3 entities in total) |
| Functional Keywords | pdgfra protein kinase, inhibitor, tyrosine kinase, transmembrane receptor, platelet-derived growth factor receptor alpha, pdgf, platelet-derived growth factor, gist, gastrointestinal stromal tumors, solvent-front mutant, p16234, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 41084.32 |
| 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 Cited by 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: 42562826DOI: 10.1038/s41467-026-76340-7 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.2 Å) |
Structure validation
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