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Discovery of potent and selective HER2 PROTAC degrader based Tucatinib with improved efficacy against HER2 positive
Mingxing Hu1, Yujue Li2, Jiaxuan Li1
1State 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.
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.
Insights
Researchers developed CH7C4, a novel selective HER2 PROTAC degrader, offering improved antitumor activity against HER2-positive cancers. This new therapeutic strategy shows promise in overcoming limitations of current treatments like tyrosine kinase inhibitors (TKIs).
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- HER2 is a key therapeutic target in HER2-positive breast and gastric cancers.
- Tyrosine kinase inhibitors (TKIs) have improved patient outcomes but cause side effects and resistance.
- Existing pan-HER TKIs exhibit gastrointestinal and skin toxicities, limiting their efficacy.
Purpose of the Study:
- To discover and characterize the first potent and selective HER2 PROTAC degrader.
- To evaluate the antitumor activity of the novel compound CH7C4 in vitro and in vivo.
- To explore CH7C4 as a potential therapeutic strategy for HER2-positive cancers.
Main Methods:
- Discovery and characterization of a selective HER2 PROTAC degrader, CH7C4.
- In vitro assessment of HER2 degradation (DC50, Dmax) and cell proliferation inhibition (IC50).
- In vivo evaluation of pharmacokinetic profiles and antitumor efficacy in xenograft models.
Main Results:
- CH7C4 demonstrated potent HER2 degradation (DC50: 69 nM, Dmax: 96%) and significant inhibition of BT-474 cell proliferation (IC50: 0.047 nM).
- CH7C4 achieved long-lasting HER2 degradation, downstream pathway repression, and favorable pharmacokinetics (half-life: 5.31 h).
- In vivo, CH7C4 significantly inhibited tumor growth in BT-474 xenografts (TGI: 73%) with improved antitumor activity compared to Tucatinib.
Conclusions:
- CH7C4 is the first selective HER2 PROTAC degrader with superior in vitro and in vivo antitumor activity.
- This novel degrader offers a promising therapeutic strategy for HER2-positive cancers, potentially overcoming TKI limitations.
- CH7C4 provides new insights for developing next-generation treatments for HER2-driven malignancies.
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