Discovery of potent epidermal growth factor receptor (EGFR) degraders by proteolysis targeting chimera (PROTAC)

Abstract

Epidermal growth factor receptor (EGFR), a member of the HER family, is closely related to the development of multiple cancers. Herein, we report the discovery of small molecule EGFR degraders based on the proteolysis targeting chimera (PROTAC) strategy. In the present study, 13 EGFR degraders containing pyrido[3,4-d] pyrimidine moiety were designed and synthesized. Promising PROTACs 2 and 10 induced degradation of EGFR in HCC827 cells with the DC₅₀ values of 45.2 and 34.8 nM, respectively. Cellular protein-controlling machinery ubiquitin proteasome system (UPS) was involved in the degradation process. Furthermore, the degraders 2 and 10 could significantly induce the apoptosis of HCC827 cells and arrest the cells in G₁ phase. These findings demonstrated that compounds 2 and 10 could serve as effective EGFR^del19-targeting degraders in HCC827 cells. v.

Keywords: EGFR-TK; EGFR-TK degraders; Proteolysis targeting chimera; pyrido[3,4-d]pyrimidine.