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Design, synthesis and biological evaluation of KRASG12C-PROTACs

文献类型：期刊论文

作者Zhang, Xiaoyi6; Zhao, Tong7; Sun, Minghao1,2; Li, Pei7; Lai, Mengzhen5; Xie, Lingfeng6; Chen, Jiaying4,5; Ding, Jian4,5; Xie, Hua3,5; Zhou, Jinpei7
刊名BIOORGANIC & MEDICINAL CHEMISTRY
出版日期2023-01-15
卷号78页码:14
关键词KRASG12C PROTAC Covalent inhibitors Structure-activity relationships (SARs) Anticancer
ISSN号0968-0896
DOI10.1016/j.bmc.2023.117153
通讯作者Xie, Hua(hxie@simm.ac.cn) ; Zhou, Jinpei(zhjp@cpu.edu.cn) ; Zhang, Huibin(zhanghb80@cpu.edu.cn)
英文摘要Several small-molecule covalent inhibitors of KRASG12C have made breakthrough progress in the treatment of KRAS mutant cancer. However, the clinical application of KRASG12C small-molecule inhibitors may be limited by adaptive resistance. Emerging PROTAC strategy can achieve complementary advantages with small molecule inhibitors and improve anti-tumor efficacy. Based on AMG-510, a series of novel KRASG12C-PROTACs were designed and synthesized. The protein degradation assay showed that PROTACs I-1, II-1, III-2 and IV-1 had binding and degradation ability to KRASG12C. III-2 and IV-1 showed potent inhibitory effect on downstream p-ERK and were more potent than AMG-510. Mechanistic studies demonstrated that PROTACs exerted degradation effects through the ubiquitin-proteasome pathway. Using cell lines sensitive to KRASG12C, anti-proliferative activities of compounds were assessed. PROTACs tested showed overall anti-proliferative activities. Besides, the structure-activity relationships (SARs) of KRASG12C-PROTACs were summarized. These results supported the use of the PROTAC strategy to degrade oncogene KRASG12C and provided clues for structural optimization of KRASG12C-PROTACs.
WOS关键词AMG 510 ; TARGETING KRAS ; RAS ; KRAS(G12C) ; PROTAC ; DEGRADATION ; DISCOVERY ; INHIBITOR ; CANCER
资助项目Lingang Laboratory[LG202103-02-08]
WOS研究方向Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
语种英语
WOS记录号WOS:000922058900001
出版者PERGAMON-ELSEVIER SCIENCE LTD
源URL[http://119.78.100.183/handle/2S10ELR8/303364]  
专题中国科学院上海药物研究所
通讯作者Xie, Hua; Zhou, Jinpei; Zhang, Huibin
作者单位1.China Pharmaceut Univ, State Key Lab Nat Med, Nanjing 210009, Peoples R China
2.China Pharmaceut Univ, Jiangsu Key Lab Drug Discovery Metab Dis, Ctr Adv Pharmaceut & Biomat, Nanjing 210009, Peoples R China
3.Chinese Acad Sci, Zhongshan Inst Drug Discovery, Shanghai Inst Mat Med, Shanghai, Peoples R China
4.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, Shanghai, Peoples R China
6.China Pharmaceut Univ, Ctr Drug Discovery, Jiangsu Key Lab Drug Discovery Metab Dis, Nanjing 210009, Peoples R China
7.China Pharmaceut Univ, Dept Med Chem, 24 Tongjiaxiang, Nanjing 210009, Peoples R China
推荐引用方式
GB/T 7714		 Zhang, Xiaoyi,Zhao, Tong,Sun, Minghao,et al. Design, synthesis and biological evaluation of KRASG12C-PROTACs[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2023,78:14.
APA Zhang, Xiaoyi.,Zhao, Tong.,Sun, Minghao.,Li, Pei.,Lai, Mengzhen.,...&Zhang, Huibin.(2023).Design, synthesis and biological evaluation of KRASG12C-PROTACs.BIOORGANIC & MEDICINAL CHEMISTRY,78,14.
MLA Zhang, Xiaoyi,et al."Design, synthesis and biological evaluation of KRASG12C-PROTACs".BIOORGANIC & MEDICINAL CHEMISTRY 78(2023):14.

入库方式： OAI收割

来源：上海药物研究所

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