2. Academic Validation
  3. Discovery of potent and selective HER2 PROTAC degrader based Tucatinib with improved efficacy against HER2 positive cancers

Discovery of potent and selective HER2 PROTAC degrader based Tucatinib with improved efficacy against HER2 positive cancers

  • Eur J Med Chem. 2022 Dec 15:244:114775. doi: 10.1016/j.ejmech.2022.114775.
Mingxing Hu 1,  Yujue Li 2,  Jiaxuan Li 1,  Haoxuan Zhou 1,  Chengyali Liu 1,  Zi Liu 1,  Youling Gong 3,  Binwu Ying 1,  Yongmei Xie 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, Department of Laboratory Medicine, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China.
  • 2 General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 3 Department of Thoracic Oncology, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 4 State Key Laboratory of Biotherapy and Cancer Center, Department of Laboratory Medicine, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, 610041, China. Electronic address: xieym@scu.edu.cn.
PMID: 36208507 DOI: 10.1016/j.ejmech.2022.114775
Abstract

HER2 is a validated therapeutic target for HER2 positive breast Cancer and gastric Cancer. TKIs have significantly improved the prognosis of patients with HER2 positive Cancer. However, the pan-HER TKIs always caused gastrointestinal and skin side effects, and acquired drug resistance inevitable compromised their therapeutic efficacy. Herein, we describe the discovery of the first potent and selective HER2 PROTAC degrader based Tucatinib with improved antitumor activity in vitro and in vivo. The preferred selective HER2 PROTAC, CH7C4, efficiently degraded HER2 with DC50 of 69 nM and Dmax of 96%, and inhibited the proliferation of BT-474 cells with IC50 of 0.047 ± 0.006 nM via long lasting HER2 degradation and strong repression of downstream pathway. Moreover, CH7C4 had acceptable pharmacokinetic profiles with a half-life of 5.31 h, and significantly inhibited the growth of BT-474 xenografts in vivo with TGI of 73%. As the first selective HER2 PROTAC degrader with better activity in vitro and in vivo than Tucatinib, CH7C4 provides new insights into the development of new therapeutic strategy for HER2 positive Cancer.

Keywords

CADD; HER2; PROTAC; Structural optimization; anti-tumor.

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