Design and synthesis of proteolysis targeting chimeras (PROTACs) as an EGFR degrader based on CO-1686.

Epidermal growth factor receptor (EGFR) inhibitors represent the first-line treatment of non-small-cell lung cancer (NSCLC). However, the emergence of acquired drug resistance and side effects largely encumbered their application in clinic. The emerging technology proteolysis targeting chimera (PROTAC) could be an alternative strategy to overcome these problems. Herein, we reported the discovery of EGFRL858R/T790M degraders based on CO-1686. Promising PROTAC 1q could effectively and selectively inhibit the growth of PC-9 (EGFRDel 19) and H1975 (EGFRL858R/T790M) cells, but not that of A549 (EGFRWT) cells. In addition, 1q could time- and dose-dependently induce degradation of EGFRL858R/T790M in H1975 cells with a DC50 value of 355.9 nM, while did not show obvious effect on the EGFRDel 19 and EGFRWT protein. Preliminary mechanism study demonstrated that the protein degradation was mediated through ubiquitin-proteasome system (UPS). Furthermore, 1q could significantly induce the apoptosis of H1975 cells and arrest the cells in G0/G1 phase. These findings demonstrated that compound 1q could be used as initial lead compound for the development of new EGFRL858R/T790M degraders based therapy.