6DUK

EGFR with an allosteric inhibitor

Summary for 6DUK

• Entry DOI: 10.2210/pdb6duk/pdb
• Descriptor: Epidermal growth factor receptor, MAGNESIUM ION, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, ... (5 entities in total)
• Functional Keywords: allosteric inhibitor, egfr, oncoprotein, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 6
• Total formula weight: 232792.27

Authors

Park, E.,Eck, M.J. (deposition date: 2018-06-21, release date: 2019-06-05, Last modification date: 2023-10-11)

Primary citation

To, C.,Jang, J.,Chen, T.,Park, E.,Mushajiang, M.,De Clercq, D.J.H.,Xu, M.,Wang, S.,Cameron, M.D.,Heppner, D.E.,Shin, B.H.,Gero, T.W.,Yang, A.,Dahlberg, S.E.,Wong, K.K.,Eck, M.J.,Gray, N.S.,Janne, P.A.
Single and Dual Targeting of Mutant EGFR with an Allosteric Inhibitor.
Cancer Discov, 9:926-943, 2019

PubMed Abstract: Allosteric kinase inhibitors offer a potentially complementary therapeutic strategy to ATP-competitive kinase inhibitors due to their distinct sites of target binding. In this study, we identify and study a mutant-selective EGFR allosteric inhibitor, JBJ-04-125-02, which as a single agent can inhibit cell proliferation and EGFR signaling and . However, increased EGFR dimer formation limits treatment efficacy and leads to drug resistance. Remarkably, osimertinib, an ATP-competitive covalent EGFR inhibitor, uniquely and significantly enhances the binding of JBJ-04-125-02 for mutant EGFR. The combination of osimertinib and JBJ-04-125-02 results in an increase in apoptosis, a more effective inhibition of cellular growth, and an increased efficacy and compared with either single agent alone. Collectively, our findings suggest that the combination of a covalent mutant-selective ATP-competitive inhibitor and an allosteric EGFR inhibitor may be an effective therapeutic approach for patients with -mutant lung cancer. SIGNIFICANCE: The clinical efficacy of EGFR tyrosine kinase inhibitors (TKI) in -mutant lung cancer is limited by acquired drug resistance, thus highlighting the need for alternative strategies to inhibit EGFR. Here, we identify a mutant EGFR allosteric inhibitor that is effective as a single agent and in combination with the EGFR TKI osimertinib..

PubMed: 31092401
DOI: 10.1158/2159-8290.CD-18-0903

Experimental method

X-RAY DIFFRACTION (2.2 Å)