2. Academic Validation
  3. Design, synthesis and biological evaluation of KRASG12C-PROTACs

Design, synthesis and biological evaluation of KRASG12C-PROTACs

  • Bioorg Med Chem. 2023 Jan 15:78:117153. doi: 10.1016/j.bmc.2023.117153.
Xiaoyi Zhang 1,  Tong Zhao 2,  Minghao Sun 3,  Pei Li 2,  Mengzhen Lai 4,  Lingfeng Xie 1,  Jiaying Chen 5,  Jian Ding 5,  Hua Xie 6,  Jinpei Zhou 7,  Huibin Zhang 8
Affiliations

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: [email protected].
  • 7 Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: [email protected].
  • 8 Center for Drug Discovery, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: [email protected].
PMID: 36621179 DOI: 10.1016/j.bmc.2023.117153
Abstract

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.

Keywords

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

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