Erianin suppresses constitutive activation of MAPK signaling pathway by inhibition of CRAF and MEK1/2  

作　　者：Penglei Wang Xuechao Jia Bingbing Lu Han Huang Jialin Liu Xuejiao Liu Qiong Wu Yamei Hu Pan Li Huifang Wei Tingting Liu Dengyun Zhao Lingwei Zhang Xueli Tian Yanan Jiang Yan Qiao Wenna Nie Xinli Ma Ruihua Bai Cong Peng Zigang Dong Kangdong Liu 

机构地区：[1]Department of Pathophysiology,Basic Medicine Research Center,School of Basic Medical Sciences,AMS,Zhengzhou University,450000 Zhengzhou,China [2]China-US(Henan)Hormel Cancer Institute,450000 Zhengzhou,China [3]The Department of Pathology,Affiliated Cancer Hospital of Zhengzhou University,450000 Zhengzhou,China [4]The Department of Dermatology,Xiangya Hospital,Central South University,410078 Changsha,China [5]The Collaborative Innovation Center of Henan Province for Cancer Chemoprevention,450000 Zhengzhou,China [6]State Key Laboratory of Esophageal Cancer Prevention and Treatment,Zhengzhou University,450000 Zhengzhou,China [7]Provincial Cooperative Innovation Center for Cancer Chemoprevention,Zhengzhou University,Zhengzhou,China

出　　处：《Signal Transduction and Targeted Therapy》2023年第4期1874-1888,共15页信号转导与靶向治疗（英文）

基　　金：the National Natural Science Foundations of China(No.81872335);The Central Plains Science and Technology Innovation Leading Talents(No.224200510015);Program for Science&Technology Innovation Talents in Universities of Henan(No.20HASTIT048);the Cultivation Foundation of Zhengzhou University(No.JC202035022)。

摘　　要：Constitutive activation of RAS-RAF-MEK-ERK signaling pathway(MAPK pathway)frequently occurs in many cancers harboring RAS or RAF oncogenic mutations.Because of the paradoxical activation induced by a single use of BRAF or MEK inhibitors,dual-target RAF and MEK treatment is thought to be a promising strategy.In this work,we evaluated erianin is a novel inhibitor of CRAF and MEK1/2 kinases,thus suppressing constitutive activation of the MAPK signaling pathway induced by BRAF V600E or RAS mutations.KinaseProfiler enzyme profiling,surface plasmon resonance(SPR),isothermal titration calorimetry(ITC),cellular thermal shift assay,computational docking,and molecular dynamics simulations were utilized to screen and identify erianin binding to CRAF and MEK1/2.Kinase assay,luminescent ADP detection assay,and enzyme kinetics assay were investigated to identify the efficiency of erianin in CRAF and MEK1/2 kinase activity.Notably,erianin suppressed BRAF V600E or RAS mutant melanoma and colorectal cancer cell by inhibiting MEK1/2 and CRAF but not BRAF kinase activity.Moreover,erianin attenuated melanoma and colorectal cancer in vivo.Overall,we provide a promising leading compound for BRAF V600E or RAS mutant melanoma and colorectal cancer through dual targeting of CRAF and MEK1/2.

关 键 词：MEK1/2 BRAF ACTIVATION 

分 类 号：R730[医药卫生—肿瘤]