Citation: Zimo Yang, Yan Tong, Yongbo Liu, Qianlong Liu, Zhihao Ni, Yuna He, Yu Rao. Developing selective PI3K degraders to modulate both kinase and non-kinase functions[J]. Chinese Chemical Letters, ;2024, 35(11): 109577. doi: 10.1016/j.cclet.2024.109577 shu

Developing selective PI3K degraders to modulate both kinase and non-kinase functions

State Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China

yrao@tsinghua.edu.cn

Received Date: 2 August 2023
Revised Date: 22 January 2024
Accepted Date: 24 January 2024
Available Online: 1 February 2024

Figures(4)

For the first time, proteolysis-targeting chimeras (PROTAC) technology was utilized to achieve the isoform-selective degradation of class Ⅰ phosphoinositide 3-kinases (PI3Ks) in this study. Through screening and optimization, the PROTAC molecule ZM-PI05 was identified as a selective degrader of p110α in multiple breast cancer cells. More importantly, the degrader can down-regulate p85 regulatory subunit simultaneously, thereby inhibiting the non-enzymatic functions of PI3K that are independent on p110 catalytic subunits. Therefore, compared with PI3K inhibitor copanlisib, ZM-PI05 displayed the stronger anti-proliferative activity on breast cancer cells. In brief, a selective and efficient PROTAC molecule was developed to induce the degradation of p110α and concurrent reduction of p85 proteins, providing a tool compound for the biological study of PI3K-α by blocking its enzymatic and non-enzymatic functions.
- PI3K,
- PROTAC,
- p110,
- p85,
- Selectivity,
- Degradation,
- Non-kinase functions
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