Celastrol suppresses colorectal cancer via covalent targeting peroxiredoxin 1  

作　　者：Heng Xu Hongfang Zhao Chunyong Ding Defang Jiang Zijie Zhao Yang Li Xiaoyu Ding Jing Gao Hu Zhou Cheng Luo Guoqiang Chen Ao Zhang Ying Xu Hao Zhang 

机构地区：[1]School of Pharmaceutical Science and Technology,Hangzhou Institute for Advanced Study,University of Chinese Academy of Sciences,Hangzhou 310024,China [2]Chemical Biology Research Center,State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China [3]CAS Key Laboratory of Tissue Microenvironment and Tumor,Shanghai Institute of Nutrition and Health,University of Chinese Academy of Sciences,Chinese Academy of Sciences,Shanghai 200031,China [4]Department of Pathophysiology,Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education,Shanghai Jiao Tong University School of Medicine,Shanghai 200025,China [5]Pharm-X center,College of Pharmaceutical Sciences,Shanghai Jiao Tong University,Shanghai 200240,China [6]School of Chinese Materia Medica,Nanjing University of Chinese Medicine,138 Xianlin Road,Qixia,Nanjing 210023 Jiangsu,China [7]University of Chinese Academy of Sciences,No.19A Yuquan Road,Beijing 100049,China [8]State Key Laboratory of Oncogenes and Related Genes,Shanghai Cancer Institute,Ren-Ji Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200127,China

出　　处：《Signal Transduction and Targeted Therapy》2023年第3期1159-1174,共16页信号转导与靶向治疗（英文）

基　　金：We are grateful to National Centre for Protein Science Shanghai for their instrument support and technical assistance.We thank the staffs from BL19U1 beamline of National Facility for Protein Science Shanghai(NFPS)at Shanghai Synchrotron Radiation Facility,for assistance during data collection.We gratefully acknowledge the financial supports from the National Key Research and Development Program of China(2020YFE0202200 to H.Z.and 2021ZD0203900 to C.L.);the project of National Multidisciplinary Innovation Team of Traditional Chinese Medicine(ZYYCXTD-202004 to C.L.);the National Natural Science Foundation of China(81903538 to H.Z.,82104064 to H.X.,91853205 to C.L.,91853206 to G.C.,81773565 to A.Z.,81972615 to Y.X.,and 21877120,22177068 to C.D.);the Postdoctoral Research Foundation of China(2019M661673 to H.Z.);the Shanghai Sailing Plan(19YF1457200 to H.Z.);the grants from Shanghai Jiao Tong University(AF1700037,WF220217002,WH101117001,and WF540162618 to A.Z.).

摘　　要：As a terpenoids natural product isolated from the plant Thunder God Vine,Celastrol is widely studied for its pharmacological activities,including anti-tumor activities.The clinical application of Celastrol is strictly limited due to its severe side effects,whereas previously revealed targets and mechanism of Celastrol seldom reduce its in vivo toxicity via structural optimization.Target identification has a far-reaching influence on the development of innovative drugs,and omics data has been widely used for unbiased target prediction.However,it is difficult to enrich target of specific phenotype from thousands of genes or proteins,especially for natural products with broad promising activities.Here,we developed a text-mining-based web-server tool to enrich targets from omics data of inquired compounds.Then peroxiredoxin 1(PRDX1)was identified as the ROS-manipulating target protein of Celastrol in colorectal cancer.Our solved high-resolution crystal structure revealed the unique covalent binding mode of Celastrol with PRDX1.New derivative compound 19-048 with improved potency against PRDX1 and selectivity towards PRDX2~PRDX6 were synthesized based on crystal structure analysis.Both Celastrol and 19-048 effectively suppressed the proliferation of colorectal cancer cells.The anti-tumor efficacy of Celastrol and 19-048 was significantly diminished on xenograft nude mice bearing PRDX1 knock-down colorectal cancer cells.Several downstream genes of p53 signaling pathway were dramatically up-regulated with Celastrol or 19-048 treatment.Our findings reveal that the side effects of Celastrol could be reduced via structural modification,and PRDX1 inhibition is promising for the treatment of colorectal cancer.

关 键 词：COLORECTAL cancer NUDE 

分 类 号：R735.37[医药卫生—肿瘤]