首页|Developing selective PI3K degraders to modulate both kinase and non-kinase functions
Developing selective PI3K degraders to modulate both kinase and non-kinase functions
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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 screen-ing 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.
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
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