Discovery of a first-in-class ANXA3 degrader for the treatment of triple-negative breast cancer  

作　　者：Yongxi Liang Delin Min Hulin Fan Kunlin Liu Juchuanli Tu Xueyan He Bingjie Liu Lu Zhou Suling Liu Xun Sun 

机构地区：[1]School of Pharmacy,Fudan University,Shanghai 201203,China [2]The Institutes of Integrative Medicine of Fudan University,Shanghai 200040,China [3]Fudan University Shanghai Cancer Center&Institutes of Biomedical Sciences,State Key Laboratory of Genetic Engineering,Fudan University,Shanghai 200032,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第4期1686-1698,共13页药学学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(Nos.82073688,82103971 and 81930075);Shanghai Science and Technology Development Fund from Central Leading Local Government(No.YDZX20223100001004,China);Science and Technology Commission of Shanghai Municipality(No.21S11907300,China);Program of Shanghai Academic/Technology Research Leader(No.20XD1400700,China)。

摘　　要：Triple-negative breast cancer(TNBC)is a nasty disease with extremely high malignancy and poor prognosis.Annexin A3(ANXA3)is a potential prognosis biomarker,displaying an excellent correlation of ANXA3 overexpression with patients'poor prognosis.Silencing the expression of ANXA3effectively inhibits the proliferation and metastasis of TNBC,suggesting that ANXA3 can be a promising therapeutic target to treat TNBC.Herein,we report a first-in-class ANXA3-targeted small molecule(R)-SL18,which demonstrated excellent anti-proliferative and anti-invasive activities to TNBC cells.(R)-SL18 directly bound to ANXA3 and increased its ubiquitination,thereby inducing ANXA3 degradation with moderate family selectivity.Importantly,(R)-SL18 showed a safe and effective therapeutic potency in a high ANXA3-expressing TNBC patient-derived xenograft model.Furthermore,(R)-SL18 could reduce theβ-catenin level,and accordingly inhibit the Wnt/β-catenin signaling pathway in TNBC cells.Collectively,our data suggested that targeting degradation of ANXA3 by(R)-SL18 possesses the potential to treat TNBC.

关 键 词：Annexin A3(ANXA3) Degrader Triple-negative breast cancer UBIQUITINATION Patient-derived xenograft 

分 类 号：R737.9[医药卫生—肿瘤]