Development of a Brigatinib degrader (SIAIS117) as a potential treatment for ALK positive cancer resistance
开发一种Brigatinib降解剂( SIAIS117 )作为ALK阳性肿瘤耐药的潜在治疗手段
作者: Ning SunChaowei RenYing KongHui ZhongJinju ChenYan LiJianshui ZhangYuedong ZhouXing QiuHaifan LinXiaoling SongXiaobao YangBiao Jiang
作者单位: 1Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China
2CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China
3Changzhou University, Changzhou, Jiangsu, 213164, China
4Yale Stem Cell Center, Yale University, New Haven, CT, 06511, USA
5Jing Medicine Technology (Shanghai), Ltd., Y building, 230 Haike Road, Shanghai, 201210, China
刊名: European Journal of Medicinal Chemistry, 2020, Vol.193
来源数据库: Elsevier Journal
DOI: 10.1016/j.ejmech.2020.112190
关键词: ALKBrigatinibDegraderVHLPROTACNSCLCALCLResistance
英文摘要: Abstract(#br)EML4-ALK and NPM-ALK fusion proteins possess constitutively activated ALK (anaplastic lymphoma kinase) activity, which in turn leads to the development of non-small cell lung cancer and anaplastic large-cell lymphomas (ALCLs). FDA-approved ALK inhibitor drugs cause significant cancer regression. However, drug resistance eventually occurs and it becomes a big obstacle in clinic. Novel proteolysis targeting chimera (PROTAC) technology platform provides a potential therapeutic strategy for drug resistance. Herein, we designed and synthesized a series of ALK PROTACs based on Brigatinib and VHL-1 conjunction, and screened SIAIS117 as the best degrader which not only blocked the growth of SR and H2228 cancer cell lines, but also degraded ALK protein. In addition, SIAIS117 also...
全文获取路径: Elsevier  (合作)
影响因子:3.499 (2012)

  • potential 
  • treatment 处理
  • cancer 癌症
  • positive 阳片
  • resistance 抵抗