顺苯磺酸阿曲库铵(51w89)作为CD73抑制剂的发现及评价  

Discovery and Evaluation of Cisatracurium Besylate(51w89)as an Inhibitor of CD73

作　　者：刘永杰 汤姜杨 朱丽丽 李洪林 LIU Yongjie;TANG Jiangyang;ZHU Lili;LI Honglin(Shanghai Key Laboratory of New Drug Design,School of Pharmacy,East China University of Science and Technology,Shanghai 200237,China)

机构地区：[1]华东理工大学药学院,上海市新药设计重点实验室,上海200237

出　　处：《华东理工大学学报（自然科学版）》2023年第2期220-226,共7页Journal of East China University of Science and Technology

基　　金：国家杰出青年科学基金(81825020)。

摘　　要：胞外5′-核苷酸酶(e5NT,又称CD73)是一个新兴的肿瘤治疗潜在靶点,与肿瘤的发生、发展、转移及不良预后密切相关。通过筛选发现顺苯磺酸阿曲库铵(51w89)可以抑制CD73的酶活性,其在分子水平的IC_(50)为(13.30±0.34)μmol/L;通过表面等离子共振实验测得51w89与CD73蛋白的结合亲和力常数(KD)为20.45μmol/L;在高表达CD73的人乳腺癌细胞MDA-MB-231中测得51w89抑制细胞中CD73的酶活性IC_(50)为(17.70±0.98)μmol/L。51w89可抑制MDA-MB-231细胞的迁移能力,并且51w89可逆转单磷酸腺苷(AMP)对CD8^(+)T细胞分泌IFN-γ的抑制作用。51w89可作为CD73潜在抑制剂用于后续的抗肿瘤研究。Over recent years,immunotherapy has developed rapidly,which has changed the way of cancer treatment.However,most patients cannot benefit from immunotherapy,because of insufficient reprogramming of the immunosuppressive tumor microenvironment(TME)which thus limits reinvigoration of antitumor immunity.In TME,adenosine,a metabolite of ATP,is an effective immunoregulatory factor.Extracellular 5'-nucleotidase(CD73)is the rate-limiting molecule in the process of adenosine production.Overexpression of CD73 on tumor cells and immune cells leads to a higher concentration of adenosine in the TME.The high concentration of adenosine suppresses the antitumor immune response,promoting tumor cells proliferate,metastasis and angiogenesis.Therefore,anti-CD73 therapy is expected to become a promising strategy for cancer immunotherapy.Several anti-CD73 mAbs(MEDI9447,BMS986179,SRF373/NZV930,CPI-006/CPX-006,IPH5301,TJ004309)and small molecule CD73 inhibitors(LY3475070,AB680,CB-708)were investigated in early phase clinical trials.But so far,there is no CD73 targeted product for the treatment of cancer on the market.In this study,we performed the screening of our compound library containing 876 listed drugs to identify candidate inhibitors targeting CD73.Preliminary experimental results showed that Cisatracurium besylate(51w89)could inhibit the enzyme activity of recombinant CD73 with an IC_(50) value of 13.30μmol/L.To verify the interactions between 51w89 and CD73 and evaluate their binding affinities,we performed surface plasmon resonance(SPR)experiments using a Biacore T200(GE Healthcare).The binding affinity(KD)of 51w89 binding to CD73 was 20.45μmol/L.Encouraged by these results at the molecular level,then we evaluated the inhibitory effect of 51w89 against CD73 in MDA-MB-231 cells.The results show that the IC_(50) of 51w89 against CD73 in MDA-MB-231 cells was(17.70±0.98)μmol/L,closing to the IC_(50) value at the molecular level.Subsequently,we proved the role of CD73 in the migration of MDA-MB-231 cells through scratch tests,t

关 键 词：CD73 抑制剂 肿瘤 迁移 CD8+T细胞 

分 类 号：R915[医药卫生—微生物与生化药学]