Discovery of novel exceptionally potent and orally active c-MET PROTACs for the treatment of tumors with MET alterations  

作　　者：Pengyun Li Changkai Jia Zhiya Fan Xiaotong Hu Wenjuan Zhang Ke Liu Shiyang Sun Haoxin Guo Ning Yang Maoxiang Zhu Xiaomei Zhuang Junhai Xiao Zhibing Zheng Song Li 

机构地区：[1]National Engineering Research Center for Strategic Drugs,Beijing Institute of Pharmacology and Toxicology Institution,Beijing 100850,China [2]State Key Laboratory of Toxicology and Medical Countermeasures,Beijing Institute of Pharmacology and Toxicology,Beijing 100850,China [3]National Center for Protein Sciences(Beijing),Beijing Institute of Lifeomics,State Key Laboratory of Proteomics,Beijing Proteome Research Center,Beijing 102206,China [4]Beijing Key Laboratory for Radiobiology,Beijing Institute of Radiation Medicine,Beijing 100850,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第6期2715-2735,共21页药学学报（英文版）

基　　金：supported by Major New Drugs Innovation and Development (2018ZX09J18102-002, China)。

摘　　要：Various c-mesenchymal-to-epithelial transition(c-MET) inhibitors are effective in the treatment of non-small cell lung cancer;however, the inevitable drug resistance remains a challenge, limiting their clinical efficacy. Therefore, novel strategies targeting c-MET are urgently required. Herein, through rational structure optimization, we obtained novel exceptionally potent and orally active c-MET proteolysis targeting chimeras(PROTACs) namely D10 and D15 based on thalidomide and tepotinib. D10 and D15 inhibited cell growth with low nanomolar IC_(50) values and achieved picomolar DC_(50) values and>99% of maximum degradation(D_(max)) in EBC-1 and Hs746T cells. Mechanistically, D10 and D15dramatically induced cell apoptosis, G1 cell cycle arrest and inhibited cell migration and invasion.Notably, intraperitoneal administration of D10 and D15 significantly inhibited tumor growth in the EBC-1 xenograft model and oral administration of D15 induced approximately complete tumor suppression in the Hs746T xenograft model with well-tolerated dose-schedules. Furthermore, D10 and D15 exerted significant anti-tumor effect in cells with c-MET^(Y1230H) and c-MET^(D1228N) mutations, which are resistant to tepotinib in clinic. These findings demonstrated that D10 and D15 could serve as candidates for the treatment of tumors with MET alterations.

关 键 词：Cancer therapy Drug design C-MET Proteolysis targeting chimeras(PROTACs) Drug resistance 

分 类 号：R969[医药卫生—药理学]