posted on 2021-10-20, 14:06authored byFlorian Wittlinger, David E. Heppner, Ciric To, Marcel Günther, Bo Hee Shin, Jaimin K. Rana, Anna M. Schmoker, Tyler S. Beyett, Lena M. Berger, Benedict-Tilman Berger, Nicolas Bauer, James D. Vasta, Cesear R. Corona, Matthew B. Robers, Stefan Knapp, Pasi A. Jänne, Michael J. Eck, Stefan A. Laufer
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
the development of successive generations of inhibitors that bind
in the ATP site. The 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 confer a 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 a significantly lower activity for wild-type EGFR (47 nM).
Additionally, this compound achieves modest cetuximab-independent
and mutant-selective cellular efficacies on the L858R (1.2 μM)
and L858R/T790M (4.4 μM) variants.