典型文献
Discovery of novel KRAS-PDEδ inhibitors with potent activity in patient-derived human pancreatic tumor xenograft models
文献摘要：
KRAS-PDEδ interaction is revealed as a promising target for suppressing the function of mutant KRAS.The bottleneck in clinical development of PDEδ inhibitors is the poor antitumor activity of known chemotypes.Here,we identified novel spiro-cyclic PDEδ inhibitors with potent antitumor ac-tivity both in vitro and in vivo.In particular,compound 361(KD=127±16 nmol/L)effectively bound to PDEδ and interfered with KRAS-PDEδ interaction.It influenced the distribution of KRAS in Mia PaCa-2 cells,downregulated the phosphorylation of t-ERK and t-AKT and promoted apoptosis of the cells.The novel inhibitor 361 exhibited significant in vivo antitumor potency in pancreatic cancer patient-derived xenograft(PDX)models.It represents a promising lead compound for investigating the druggability of KRAS-PDEδ interaction.
文献关键词：
中图分类号：
作者姓名：
Long Chen;Jing Zhang;Xinjing Wang;Yu Li;Lu Zhou;Xiongxiong Lu;Guoqiang Dong;Chunquan Sheng
作者机构：
School of Pharmacy,Second Military Medical University,Shanghai 200433,China;Department of Pathology,Changzheng Hospital,Second Military Medical University,Shanghai 200003,China;Department of General Surgery,Pancreatic Disease Center Ruijin Hospital,Shanghai Jiao Tong University,Shanghai 200025,China;Research Institute of Pancreatic Diseases,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China;Department of Medicinal Chemistry,School of Pharmacy,Fudan University,Shanghai 201203,China
文献出处：
引用格式：
[1]Long Chen;Jing Zhang;Xinjing Wang;Yu Li;Lu Zhou;Xiongxiong Lu;Guoqiang Dong;Chunquan Sheng-.Discovery of novel KRAS-PDEδ inhibitors with potent activity in patient-derived human pancreatic tumor xenograft models)[J].药学学报（英文版）,2022(01):274-290
A类：
Mia,druggability
B类：
Discovery,novel,KRAS,PDE,inhibitors,potent,activity,patient,derived,human,pancreatic,xenograft,models,interaction,revealed,as,promising,target,suppressing,function,mutant,bottleneck,clinical,development,poor,antitumor,known,chemotypes,Here,we,identified,spiro,cyclic,both,vitro,vivo,In,particular,compound,KD,nmol,effectively,bound,interfered,It,influenced,distribution,PaCa,cells,downregulated,phosphorylation,ERK,AKT,promoted,apoptosis,exhibited,significant,potency,cancer,PDX,represents,lead,investigating
AB值：
0.531755
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机标中图分类号，由域田数据科技根据网络公开资料自动分析生成，仅供学习研究参考。
