9GZH

PDGFRA-T674I in complex with covalent ponatinib derivative 19

This is a non-PDB format compatible entry.

Summary for 9GZH

• Entry DOI: 10.2210/pdb9gzh/pdb
• Descriptor: Platelet-derived growth factor receptor alpha, 3-(2-imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-~{N}-[4-(propanoylamino)-3-(trifluoromethyl)phenyl]benzamide (3 entities in total)
• Functional Keywords: platelet-derived growth factor receptor alpha, pdgfra, gist, gastrointestinal stromal tumor, ponatinib, gatekeeper mutation, covalent drugs, drug resistance, resistance mutation, secondary mutation, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 40929.06

Authors

Teuber, A.,Rauh, D.,Mueller, M.P. (deposition date: 2024-10-04, release date: 2025-02-12, Last modification date: 2025-02-26)

Primary citation

Schulz, T.,Gontla, R.,Teuber, A.,Beerbaum, M.,Fletcher, B.S.,Muhlenberg, T.,Kaitsiotou, H.,Hardick, J.,Jeyakumar, K.,Keul, M.,Muller, M.P.,Sievers, S.,Bauer, S.,Rauh, D.
Design, Synthesis, and SAR of Covalent KIT and PDGFRA Inhibitors─Exploring Their Potential in Targeting GIST.
J.Med.Chem., 68:3238-3259, 2025

PubMed Abstract: Gastrointestinal stromal tumors (GIST), driven by KIT and PDGFRA mutations, are the most common mesenchymal tumors of the gastrointestinal tract. Although tyrosine kinase inhibitors (TKIs) have advanced treatment, resistance mutations and off-target toxicity limit their efficacy. This study develops covalent TKIs targeting drug-resistant GIST through structure-based design, synthesis, and biological evaluation. SAR studies provided key insights into mutant KIT and PDGFRA interactions, and the first crystal structure of PDGFRA bound to a covalent inhibitor is reported. These findings highlight the promise of covalent inhibitors for overcoming resistance and advancing safer, more effective therapies for advanced GIST.

PubMed: 39841084
DOI: 10.1021/acs.jmedchem.4c02472

Experimental method

X-RAY DIFFRACTION (2.2 Å)