8H7X
Crystal structure of EGFR T790M/C797S mutant in complex with brigatinib
Summary for 8H7X
| Entry DOI | 10.2210/pdb8h7x/pdb |
| Descriptor | Epidermal growth factor receptor, 5-chloro-N~4~-[2-(dimethylphosphoryl)phenyl]-N~2~-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}pyrimidine-2,4-diamine (2 entities in total) |
| Functional Keywords | inhibitor, complex, protein kinase, signaling protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 75739.05 |
| Authors | Kukimoto-Niino, M.,Shirouzu, M. (deposition date: 2022-10-21, release date: 2023-10-25, Last modification date: 2024-03-06) |
| Primary citation | Suzuki, M.,Uchibori, K.,Oh-Hara, T.,Nomura, Y.,Suzuki, R.,Takemoto, A.,Araki, M.,Matsumoto, S.,Sagae, Y.,Kukimoto-Niino, M.,Kawase, Y.,Shirouzu, M.,Okuno, Y.,Nishio, M.,Fujita, N.,Katayama, R. A macrocyclic kinase inhibitor overcomes triple resistant mutations in EGFR-positive lung cancer. NPJ Precis Oncol, 8:46-46, 2024 Cited by PubMed Abstract: Brigatinib-based therapy was effective against osimertinib-resistant EGFR C797S mutants and is undergoing clinical studies. However, tumor relapse suggests additional resistance mutations might emerge. Here, we first demonstrated the binding mode of brigatinib to the EGFR-T790M/C797S mutant by crystal structure analysis and predicted brigatinib-resistant mutations through a cell-based assay including N-ethyl-N-nitrosourea (ENU) mutagenesis. We found that clinically reported L718 and G796 compound mutations appeared, consistent with their proximity to the binding site of brigatinib, and brigatinib-resistant quadruple mutants such as EGFR-activating mutation/T790M/C797S/L718M were resistant to all the clinically available EGFR-TKIs. BI-4020, a fourth-generation EGFR inhibitor with a macrocyclic structure, overcomes the quadruple and major EGFR-activating mutants but not the minor mutants, such as L747P or S768I. Molecular dynamics simulation revealed the binding mode and affinity between BI-4020 and EGFR mutants. This study identified potential therapeutic strategies using the new-generation macrocyclic EGFR inhibitor to overcome the emerging ultimate resistance mutants. PubMed: 38396251DOI: 10.1038/s41698-024-00542-9 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.404 Å) |
Structure validation
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