Pomalidomide hybrids act as proteolysis targeting chimeras: Synthesis,anticancer activity and B-Raf degradation |
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| Institution: | 1. School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, University town, Waihuan Rd., Panyu, Guangzhou, 510006, China;2. Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 200241, Shanghai, China;3. School of Pharmaceutical Sciences, South-Central University for nationalities, Wuhan, 430074, China;4. Department of Pharmaceutical Production Center ＆TCM and Ethnomedicine Development International Laboratory, The First Hospital of Hunan University of Chinese Medicine, 95, Shaoshan Rd, Changsha, Hunan, 41007, China;5. College of Forestry and Landscape Architecture, South China Agricultural University, 510642, China;6. Key Laboratory of Veterinary Chemical Drugs and Pharmaceutics, Ministry of Agriculture and Rural Affairs, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, P.R. China;1. School of Pharmacy, University of Wisconsin-Madison, Madison, WI 53705, USA;2. Department of Pharmaceutical Engineering, Shenyang University of Chemical Technology, Liaoning 110042, China (current address);3. Department of Chemistry, National Cheng Kung University, Tainan 701, Taiwan (current address);4. Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA;1. College of Science, Hunan Agricultural University, Furong Rd, Changsha, 410128, China;2. Department of Pharmaceutical Production Center, The First Affiliated Hospital of Hunan University of Chinese Medicine, 95, Shaoshan Rd, Changsha, Hunan, 41007, China;3. School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, E. 232, University Town, Waihuan Rd, Panyu, Guangzhou, 510006, China;4. Department of Pharmacy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, China;1. Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China;2. School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China;3. University of Chinese Academy of Sciences, Beijing, 100049, China;4. School of Physical Science and Technology, ShanghaiTech University, Shanghai, 201210, China;5. CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China;6. Changzhou University, Changzhou, Jiangsu, 213164, China;7. Jing Medicine Technology (Shanghai), Ltd., Y building230 Haike Road, Shanghai, 201210, China;1. Institute of Chemical Industry of Forest Products, Chinese Academy of Forest, Nanjing 210042, Jiangsu, PR China;2. National Engineering Laboratory for Rice and By-products Processing, Food Science and Engineering College, Central South University of Forestry and Technology, Changsha 410004, Hunan, PR China;3. Novosibirsk Institute of Organic Chemistry, Acad. Lavrentyev ave. 9, Novosibirsk 630090, Russia;4. Institute of Tropical Medicine & the Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 501405, PR China;5. School of Computer Science and Engineering, Hunan University, Changsha 410012, PR China;1. Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon, 305-600, Republic of Korea;2. College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea;3. Medicinal Chemistry and Pharmacology, Korea University of Science and Technology, Daejeon 305-350, Republic of Korea d Korea Chemical Bank, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon, 305-600, Republic of Korea |
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| Abstract: | As the first intracellular signaling molecule and the most frequently mutated oncogene, B-Raf represents an important target in cancer therapy. Here we report several pomalidomide hybrids acting as proteolysis targeting chimeras (PROTACs) for the degradation of B-Raf. Due to its high expression of B-Raf, MCF-7 cells are sensitive to these compounds. Among them, compound 2 can effectively kill cancer cells via inducing cells apoptosis. As a B-Raf degrader, compound 2 can accelerate the degradation of B-Raf by recruiting ubiquitin-proteasome system, and further affects the expression of Mcl-1, a downstream protein of B-Raf. The anticancer mechanism of compound 2 is quite different from its mother compound and cancer cells seem to be more sensitive to the degrader, hinting that degradation of B-Raf by PROTAC is a potential way for cancer treatment. |
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| Keywords: | Pomalidomide Proteolysis targeting chimeras B-Raf Anticancer activity |
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