Design, synthesis and biological evaluation of KRASG12C-PROTACs

Xiaoyi Zhang; Tong Zhao; Minghao Sun; Pei Li; Mengzhen Lai; Lingfeng Xie; Jiaying Chen; Jian Ding; Hua Xie; Jinpei Zhou; Huibin Zhang

doi:10.1016/j.bmc.2023.117153

Design, synthesis and biological evaluation of KRAS^G12C-PROTACs

Bioorg Med Chem. 2023 Jan 15:78:117153. doi: 10.1016/j.bmc.2023.117153. Epub 2023 Jan 4.

Authors

Xiaoyi Zhang¹, Tong Zhao², Minghao Sun³, Pei Li², Mengzhen Lai⁴, Lingfeng Xie¹, Jiaying Chen⁵, Jian Ding⁵, Hua Xie⁶, Jinpei Zhou⁷, Huibin Zhang⁸

Affiliations

¹ Center for Drug Discovery, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing 210009, PR China.
² Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
³ State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing 210009, PR China.
⁴ Division of Antitumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, PR China.
⁵ Division of Antitumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, PR China.
⁶ Division of Antitumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, PR China; Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, PR China. Electronic address: hxie@simm.ac.cn.
⁷ Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: zhjp@cpu.edu.cn.
⁸ Center for Drug Discovery, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: zhanghb80@cpu.edu.cn.

PMID: 36621179
DOI: 10.1016/j.bmc.2023.117153

Abstract

Several small-molecule covalent inhibitors of KRAS^G¹²^C have made breakthrough progress in the treatment of KRAS mutant cancer. However, the clinical application of KRAS^G¹²^C 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 KRAS^G¹²^C-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 KRAS^G¹²^C. 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 KRAS^G¹²^C, anti-proliferative activities of compounds were assessed. PROTACs tested showed overall anti-proliferative activities. Besides,the structure-activity relationships (SARs) of KRAS^G¹²^C-PROTACs were summarized. These results supported the use of the PROTAC strategy to degrade oncogene KRAS^G¹²^C and provided clues for structural optimization of KRAS^G¹²^C-PROTACs.

Keywords: Anticancer; Covalent inhibitors; KRAS(G)(12)(C); PROTAC; Structure-activity relationships (SARs).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Humans
Neoplasms* / drug therapy
Proteolysis
Proteolysis Targeting Chimera*
Proto-Oncogene Proteins p21(ras) / genetics

Substances

Proteolysis Targeting Chimera
Proto-Oncogene Proteins p21(ras)
KRAS protein, human