Design of a “two-in-one” mutant-selective EGFR inhibitor that spans the orthosteric and allosteric sites

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 development of successive...

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Published inJournal of medicinal chemistry Vol. 65; no. 2; pp. 1370 - 1383
Main Authors Wittlinger, Florian, Heppner, David E., To, Ciric, Günther, Marcel, Shin, Bo Hee, Rana, Jaimin K., Schmoker, Anna M., Beyett, Tyler S., Berger, Lena M., Berger, Benedict-Tilman, Bauer, Nicolas, Vasta, James D., Corona, Cesear R., Robers, Matthew B., Knapp, Stefan, Jänne, Pasi A., Eck, Michael J., Laufer, Stefan A.
Format Journal Article
LanguageEnglish
Published 20.10.2021
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Summary: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 development of successive generations of inhibitors that bind in the ATP-site. 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 confers 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 significantly lower activity for wild-type EGFR (47 nM). Additionally, this compound achieves modest cetuximab-independent, mutant-selective cellular efficacy on the L858R (1.2 μM) and L858R/T790M (4.4 μM) variants.
Bibliography:F.W., D.E.H., C.T., M.G., B.H.S., J.K.R., A.M.S., T.S.B., L.M.B., B.T.B., N.B., J.V., C.C., M.R., S.K., P.A.J., M.J.E. and S.A.L. conceived and designed the experiments
These authors contributed equally.
J.V. and B.T.B. established the NanoBRET assay
C.C., N.B. and F.W. synthesized the EGFR Tracer
L.M.B. tested the inhibitors in NanoBRET assay
F.W. and M.G. performed synthesis
J.V., C.C., and M.R. designed the NanoBRET EGFR target engagement tracer and assay
D.E.H. performed X-ray crystallography
D.E.H., C.T., B.H.S., J.K.R., T.S.B. performed biological assays
A.M.S. performed mass spectrometry experiments
F.W., D.E.H., C.T., M.G., M.J.E. and S.A.L. interpreted the data
F.W., D.E.H., M.J.E. and S.A.L. wrote the paper.
The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.
Author Contributions
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.1c00848