8TO3
EGFR(T790M/V948R) in complex with LN5461
Summary for 8TO3
| Entry DOI | 10.2210/pdb8to3/pdb |
| Descriptor | Epidermal growth factor receptor, MAGNESIUM ION, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, ... (5 entities in total) |
| Functional Keywords | cancer, inhibitor, kinase, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 4 |
| Total formula weight | 152231.83 |
| Authors | Chitnis, S.P.,Pham, C.D.,Heppner, D.E. (deposition date: 2023-08-02, release date: 2024-08-28, Last modification date: 2025-03-12) |
| Primary citation | Wittlinger, F.,Chitnis, S.P.,Pham, C.D.,Damghani, T.,Patel, K.B.,Mollers, M.,Schaeffner, I.K.,Abidakun, O.A.,Deng, M.Q.,Ogboo, B.C.,Rasch, A.,Beyett, T.S.,Buckley, B.,Feru, F.,Shaurova, T.,Knappe, C.,Eck, M.J.,Hershberger, P.A.,Scott, D.A.,Brandt, A.L.,Laufer, S.A.,Heppner, D.E. Tilting the Scales toward EGFR Mutant Selectivity: Expanding the Scope of Bivalent "Type V" Kinase Inhibitors. J.Med.Chem., 67:21438-21469, 2024 Cited by PubMed Abstract: Binding multiple sites within proteins with bivalent compounds is a strategy for developing uniquely active agents. A new class of dual-site inhibitors has emerged targeting the epidermal growth factor receptor (EGFR) anchored to both the orthosteric (ATP) and allosteric sites. Despite proof-of-concept successes, enabling selectivity against oncogenic activating mutations has not been achieved and classifying these inhibitors among kinase inhibitors remains underexplored. This study investigates the structure-activity relationships, binding modes, and biological activity of ATP-allosteric bivalent inhibitors (AABIs). We find that AABIs selectively inhibit drug-resistant EGFR mutants (L858R/T790M and L858R/T790M/C797S) by anchoring a methyl isoindolinone moiety along the αC-helix channel of the allosteric site. In contrast, related Type I/ inhibitors target wild-type EGFR but are less effective against resistant mutants. This shift in selectivity demonstrates that mutant-selective AABIs classify as "Type V" bivalent inhibitors. PubMed: 39626019DOI: 10.1021/acs.jmedchem.4c02311 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.49 Å) |
Structure validation
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