1区 · 医学
Article
作者: Shin, Bo Hee ; Bauer, Nicolas ; Berger, Lena M. ; Knapp, Stefan ; Heppner, David E. ; Rana, Jaimin K. ; Corona, Cesear R. ; Laufer, Stefan A. ; To, Ciric ; Robers, Matthew B. ; Vasta, James D. ; Berger, Benedict-Tilman ; Beyett, Tyler S. ; Wittlinger, Florian ; Günther, Marcel ; Jänne, Pasi A. ; Eck, Michael J. ; Schmoker, Anna M.
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.