6S9B

EGFR-KINASE IN COMPLEX WITH COMPOUND 1

Summary for 6S9B

• Entry DOI: 10.2210/pdb6s9b/pdb
• Descriptor: Epidermal growth factor receptor, 3-fluoranyl-~{N}-[1-(2-methyl-2-oxidanyl-propyl)benzimidazol-2-yl]-5-pyridin-3-yl-benzamide (2 entities in total)
• Functional Keywords: egf receptor kinase mutant t790m, l858r, inhibitor, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 37551.47

Authors

Bader, G. (deposition date: 2019-07-12, release date: 2019-11-20, Last modification date: 2024-05-15)

Primary citation

Engelhardt, H.,Bose, D.,Petronczki, M.,Scharn, D.,Bader, G.,Baum, A.,Bergner, A.,Chong, E.,Dobel, S.,Egger, G.,Engelhardt, C.,Ettmayer, P.,Fuchs, J.E.,Gerstberger, T.,Gonnella, N.,Grimm, A.,Grondal, E.,Haddad, N.,Hopfgartner, B.,Kousek, R.,Krawiec, M.,Kriz, M.,Lamarre, L.,Leung, J.,Mayer, M.,Patel, N.D.,Simov, B.P.,Reeves, J.T.,Schnitzer, R.,Schrenk, A.,Sharps, B.,Solca, F.,Stadtmuller, H.,Tan, Z.,Wunberg, T.,Zoephel, A.,McConnell, D.B.
Start Selective and Rigidify: The Discovery Path toward a Next Generation of EGFR Tyrosine Kinase Inhibitors.
J.Med.Chem., 62:10272-10293, 2019

PubMed Abstract: The epidermal growth factor receptor (EGFR), when carrying an activating mutation like del19 or L858R, acts as an oncogenic driver in a subset of lung tumors. While tumor responses to tyrosine kinase inhibitors (TKIs) are accompanied by marked tumor shrinkage, the response is usually not durable. Most patients relapse within two years of therapy often due to acquisition of an additional mutation in EGFR kinase domain that confers resistance to TKIs. Crucially, oncogenic EGFR harboring both resistance mutations, T790M and C797S, can no longer be inhibited by currently approved EGFR TKIs. Here, we describe the discovery of , which is a noncovalent, wild-type EGFR sparing, macrocyclic TKI. potently inhibits the above-described EGFR variants and induces tumor regressions in a cross-resistant EGFR xenograft model. Key was the identification of a highly selective but moderately potent benzimidazole followed by complete rigidification of the molecule through macrocyclization.

PubMed: 31689114
DOI: 10.1021/acs.jmedchem.9b01169

Experimental method

X-RAY DIFFRACTION (3.25 Å)