Design, Synthesis, and Biological Evaluation of Novel EGFR PROTACs Targeting Del19/T790M/C797S Mutation

The tertiary epidermal growth factor receptor (EGFR) C797S mutation predominates in the acquired mutational resistance in cancer patients to third-generation EGFR inhibitors. Small-molecule inhibitors targeting the EGFR C797S mutation have been developed with good efficiency. However, these compounds may still induce new EGFR mutations to evade the inhibition pathway. One EGFR protein degrader based on an allosteric inhibitor has shown some benefits of degrading the EGFR L858R/T790M/C797S triple mutant. However, the degrader of the other important triple EGFR mutation Del19/T790M/C797S has not been reported. Here we present the design and synthesis of a series of EGFR proteolysis-targeting chimeras (PROTACs) that can rapidly and potently induce EGFR degradation in Ba/F3 cells expressing the EGFR(Del19/T79M/C797S )mutant. One representative compound 6h time- and dose-dependently induced EGFR degradation with a DC50 of 8 nM. It also showed good antiproliferation activity (IC50 = 0.02 mu M) against Ba/F3-EGFR(Del19/T790M/C797S) cells. 6h may serve as a lead compound to develop therapeutic agents for the treatment of resistant non-small cell lung cancer patients with EGFR C797S mutants.

Automated summary

A series of EGFR proteolysis-targeting chimeras (PROTACs) were designed and synthesized to induce degradation of EGFR C797S mutant in resistant non-small cell lung cancer patients, with compound 6h showing promising degradation and antiproliferation activity.