2. Academic Validation
  3. Discovery of potent epidermal growth factor receptor (EGFR) degraders by proteolysis targeting chimera (PROTAC)

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

  • Eur J Med Chem. 2020 Mar 1;189:112061. doi: 10.1016/j.ejmech.2020.112061.
Hao Zhang 1,  Hong-Yi Zhao 1,  Xiao-Xiao Xi 1,  Yan-Jie Liu 1,  Minhang Xin 1,  Shuai Mao 1,  Jun-Jie Zhang 2,  A-Xin Lu 3,  San-Qi Zhang 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, PR China.
  • 2 School of Science, Xi'an Jiaotong University, Xi'an, Shaanxi, 710049, PR China.
  • 3 Instrumental Analysis Center of Xi'an Jiaotong University, Xi'an, Shaanxi, 710049, PR China.
  • 4 Department of Medicinal Chemistry, School of Pharmacy, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, PR China. Electronic address: [email protected].
PMID: 31951960 DOI: 10.1016/j.ejmech.2020.112061
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 EGFRdel19-targeting degraders in HCC827 cells. v.

Keywords

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

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