6Z4B

Crystal Structure of EGFR-T790M/V948R in Complex with Osimertinib and EAI045

Summary for 6Z4B

• Entry DOI: 10.2210/pdb6z4b/pdb
• Descriptor: Epidermal growth factor receptor, ~{N}-[2-[2-(dimethylamino)ethyl-methyl-amino]-4-methoxy-5-[[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino]phenyl]propanamide, (2R)-2-(5-fluoro-2-hydroxyphenyl)-2-(1-oxo-1,3-dihydro-2H-isoindol-2-yl)-N-(1,3-thiazol-2-yl)acetamide, ... (5 entities in total)
• Functional Keywords: egfr, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 78658.49

Authors

Niggenaber, J.,Mueller, M.P.,Rauh, D. (deposition date: 2020-05-25, release date: 2020-11-11, Last modification date: 2024-01-24)

Primary citation

Niggenaber, J.,Heyden, L.,Grabe, T.,Muller, M.P.,Lategahn, J.,Rauh, D.
Complex Crystal Structures of EGFR with Third-Generation Kinase Inhibitors and Simultaneously Bound Allosteric Ligands.
Acs Med.Chem.Lett., 11:2484-2490, 2020

PubMed Abstract: Osimertinib is a third-generation tyrosine kinase inhibitor (TKI) and currently the gold-standard for the treatment of patients suffering from non-small cell lung cancer (NSCLC) harboring T790M-mutated epidermal growth factor receptor (EGFR). The outcome of the treatment, however, is limited by the emergence of the C797S resistance mutation. Allosteric inhibitors have a different mode of action and were developed to overcome this limitation. However, most of these innovative molecules are not effective as a single agent. Recently, mutated EGFR was successfully addressed with osimertinib combined with the allosteric inhibitor JBJ-04-125-02, but surprisingly, structural insights into their binding mode were lacking. Here, we present the first complex crystal structures of mutant EGFR in complex with third-generation inhibitors such as osimertinib and mavelertinib in the presence of simultaneously bound allosteric inhibitors. These structures highlight the possibility of further combinations targeting EGFR and lay the foundation for hybrid inhibitors as next-generation TKIs.

PubMed: 33335671
DOI: 10.1021/acsmedchemlett.0c00472

Experimental method

X-RAY DIFFRACTION (2.5 Å)