6WAK
A crystal structure of EGFR(T790M/V948R) in complex with LN3754
Summary for 6WAK
| Entry DOI | 10.2210/pdb6wak/pdb |
| Descriptor | Epidermal growth factor receptor, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, MAGNESIUM ION, ... (5 entities in total) |
| Functional Keywords | cancer, transferase, inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 4 |
| Total formula weight | 152097.65 |
| Authors | Heppner, D.E.,Eck, M.J. (deposition date: 2020-03-25, release date: 2021-03-31, Last modification date: 2023-10-18) |
| Primary citation | Wittlinger, F.,Heppner, D.E.,To, C.,Gunther, M.,Shin, B.H.,Rana, J.K.,Schmoker, A.M.,Beyett, T.S.,Berger, L.M.,Berger, B.T.,Bauer, N.,Vasta, J.D.,Corona, C.R.,Robers, M.B.,Knapp, S.,Janne, P.A.,Eck, M.J.,Laufer, S.A. Design of a "Two-in-One" Mutant-Selective Epidermal Growth Factor Receptor Inhibitor That Spans the Orthosteric and Allosteric Sites. J.Med.Chem., 65:1370-1383, 2022 Cited by PubMed Abstract: Inhibitors targeting the epidermal growth factor receptor (EGFR) are an effective therapy for patients with non-small cell lung cancer harboring drug-sensitive activating mutations in the EGFR kinase domain. Drug resistance due to treatment-acquired mutations has motivated the development of successive generations of inhibitors that bind in the ATP site. The third-generation agent osimertinib is now a first-line treatment for this disease. Recently, allosteric inhibitors have been developed to overcome drug-resistant mutations that confer a resistance to osimertinib. Here, we present the structure-guided design and synthesis of a mutant-selective lead compound, which consists of a pyridinyl imidazole-fused benzylisoindolinedione scaffold that simultaneously occupies the orthosteric and allosteric sites. The compound potently inhibits enzymatic activity in L858R/T790M/C797S mutant EGFR (4.9 nM), with a significantly lower activity for wild-type EGFR (47 nM). Additionally, this compound achieves modest cetuximab-independent and mutant-selective cellular efficacies on the L858R (1.2 μM) and L858R/T790M (4.4 μM) variants. PubMed: 34668706DOI: 10.1021/acs.jmedchem.1c00848 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.4 Å) |
Structure validation
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