Discovery of novel anti-breast cancer agents derived from deguelin as inhibitors of heat shock protein 90 (HSP90) |
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| Institution: | 1. College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea;2. School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 16419, Republic of Korea;3. Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 152-703, Republic of Korea;4. Brain Korea 21 Program for Biomedical Science, Korea University College of Medicine, Korea University, Seoul 152-703, Republic of Korea;5. Department of Biomedical Research Center, Korea University Guro Hospital, Korea University, Seoul 152-703, Republic of Korea;1. Food and Pharmacy College, Zhejiang Ocean University, Zhejiang, Zhoushan 316022, PR China;2. Key Laboratory of Natural Resource of the Changbai Mountain and Functiaonal Molecules, Ministry of Education, Yanbian University, Jilin Yanji 133000, China;1. Department of Pharmaceutical Chemistry, Gokaraju Rangaraju College of Pharmacy, Bachupally, Kukatpally, Hyderabad 500090, India;2. Department of Pharmacology, National Institute of Pharmaceutical Education and Research, Balanagar, Hyderabad 500042, India;3. Department of Chemistry, University College of Science and Faculty of Pharmacy, Osmania University, Hyderabad 500007, India;1. Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250012, PR China;2. Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021 PR China;3. State Key Laboratory of Microbial Technology, Shandong University, Jinan, Shandong 250100, PR China;1. New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, South Korea;2. Department of Biological Sciences, Ulsan National Institutes of Science and Technology (UNIST), Ulsan 44919, South Korea;3. College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, South Korea;4. Western Seoul Center, Korea Basic Science Institute, Seoul 03760, South Korea;1. Research Laboratories, Ildong Pharmaceutical Co., Hwaseong-si, Gyeonggi-do 18449, South Korea;2. AIMS BioScience Co., 2, Baumoe-ro 27-gil, Seocho-gu, Seoul 06752, South Korea;3. Laboratory of Medicinal Chemistry, College of Pharmacy, Seoul National University, Seoul 08826, South Korea |
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| Abstract: | A series of O-substituted analogues of the B,C-ring truncated scaffold of deguelin were designed as C-terminal inhibitors of heat shock protein 90 (HSP90) and investigated as novel antiproliferative agents against HER2-positive breast cancer. Among the synthesized compounds, compound 80 exhibited significant inhibition in both trastuzumab-sensitive and trastuzumab-resistant breast cancer cells, whereas compound 80 did not show any cytotoxicity in normal cells. Compound 80 markedly downregulated the expression of the major client proteins of HSP90 in both cell types, indicating that the cytotoxicity of 80 in breast cancer cells is attributed to the destabilization and inactivation of HSP90 client proteins and that HSP90 inhibition represents a promising strategy to overcome trastuzumab resistance. A molecular docking study of 80 with the homology model of a HSP90 homodimer showed that 80 fit nicely in the C-terminal domain with a higher electrostatic complementary score than that of ATP. |
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| Keywords: | HER2-positive breast cancer Human epidermal growth factor receptor 2 Heat shock protein 90 Deguelin |
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