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 EGFRDel19/T790M/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 μM)
against Ba/F3-EGFRDel19/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.