7U9A

EGFR in complex with a macrocyclic inhibitor

Summary for 7U9A

• Entry DOI: 10.2210/pdb7u9a/pdb
• Descriptor: Epidermal growth factor receptor, 4-(5-chloro-4-fluoro-2-hydroxyanilino)-7-methoxyquinazolin-6-ol, CITRATE ANION, ... (4 entities in total)
• Functional Keywords: egfr, kinase, macrocycle, inhibitor, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 38161.26

Authors

Beyett, T.S.,Eck, M.J. (deposition date: 2022-03-10, release date: 2022-11-23, Last modification date: 2023-10-25)

Primary citation

Amrhein, J.A.,Beyett, T.S.,Feng, W.W.,Kramer, A.,Weckesser, J.,Schaeffner, I.K.,Rana, J.K.,Janne, P.A.,Eck, M.J.,Knapp, S.,Hanke, T.
Macrocyclization of Quinazoline-Based EGFR Inhibitors Leads to Exclusive Mutant Selectivity for EGFR L858R and Del19.
J.Med.Chem., 65:15679-15697, 2022

PubMed Abstract: Activating mutations in the epidermal growth factor receptor (EGFR) are frequent oncogenic drivers of non-small-cell lung cancer (NSCLC). The most frequent alterations in EGFR are short in-frame deletions in exon 19 (Del19) and the missense mutation L858R, which both lead to increased activity and sensitization of NSCLC to EGFR inhibition. The first approved EGFR inhibitors used for first-line treatment of NSCLC, gefitinib and erlotinib, are quinazoline-based. However, both inhibitors have several known off-targets, and they also potently inhibit wild-type (WT) EGFR, resulting in side effects. Here, we applied a macrocyclic strategy on a quinazoline-based scaffold as a proof-of-concept study with the goal of increasing kinome-wide selectivity of this privileged inhibitor scaffold. Kinome-wide screens and SAR studies yielded , a potent inhibitor for the most common EGFR mutation (EGFR Del19: 119 nM) with selectivity against the WT receptor (EGFR: >10 μM) and the kinome.

PubMed: 36384036
DOI: 10.1021/acs.jmedchem.2c01041

Experimental method

X-RAY DIFFRACTION (2.6 Å)