Design and synthesis of 2-amino-6-(1H,3H-benzo[de]isochromen-6-yl)-1,3,5-triazines as novel Hsp90 inhibitors |
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| Affiliation: | 1. Research Division, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan;2. Discovery Research Center, C&C Research Laboratories, DRC Natural Sciences Campus, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon-si, Gyeonggi-do 440-746, Republic of Korea;1. College of Chemistry and Environmental Science, Key Laboratory of Chemical Biology of Hebei Province, Hebei University, Baoding 071002, PR China;2. Printable Electronics Research Centre, Suzhou Institute of Nanotech and Nano-bionics, Chinese Academy of Sciences, Suzhou 215123, PR China;3. School of Chemistry and Chemical Engineering of University of Chinese Academy of Sciences, Beijing 100049, PR China;1. Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, N. T., Hong Kong SAR, China;2. State Key Laboratory of Phytochemistry and Plant Resources in West China (CUHK), The Chinese University of Hong Kong, Shatin, N. T., Hong Kong SAR, China;3. School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, N. T., Hong Kong SAR, China;4. School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Kowloon, Hong Kong SAR, China;5. State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China;1. Department of Organic Chemistry, Faculty of Chemistry, Bu-Ali Sina University, 65174, Hamedan, Iran;2. Department of Chemistry, Faculty of Sciences, Ilam University, Ilam 69315516, Iran;1. Nofima Mat, Oslovegen 1, 1430 Ås, Norway;2. Dept of Food Science, University of Copenhagen, Denmark;3. SINTEF, Fisheries and Aquaculture Ltd., P.O. Box 7465, Trondheim, Norway;4. Mills DA, P.O. Box 4644, Sofienberg, 0506 Oslo, Norway;1. Institute of Molecular and Crystal Engineering, College of Chemistry and Chemical Engineering, Henan University, Kaifeng, Henan 475004, PR China;2. School of Chemistry, Key Laboratory of Cluster Science, Ministry of Education of China, Beijing Institute of Technology, Beijing 100081, PR China;1. School of Health Sciences, University of KwaZulu-Natal, Durban 4001, South Africa;2. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia;3. Department of Zoology, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia;4. School of Laboratory of Medicine and Medical Sciences, University of KwaZulu-Natal, Durban 4001, South Africa;5. Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia;6. School of Chemistry and Physics, University of KwaZulu-Natal, Durban 4001, South Africa;7. Department of Organic Chemistry, University of Barcelona, Barcelona 08028, Spain;8. CIBER-BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Barcelona Science Park, Barcelona 08028, Spain;9. Chemistry Department, Faculty of Science, Alexandria University, P.O. Box 426, Ibrahimia, 12321 Alexandria, Egypt |
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| Abstract: | A novel series of 2-amino-1,3,5-triazines bearing a tricyclic moiety as heat shock protein 90 (Hsp90) inhibitors is described. Molecular design was performed using X-ray cocrystal structures of the lead compound CH5015765 and natural Hsp90 inhibitor geldanamycin with Hsp90. We optimized affinity to Hsp90, in vitro cell growth inhibitory activity, water solubility, and liver microsomal stability of inhibitors and identified CH5138303. This compound showed high binding affinity for N-terminal Hsp90α (Kd = 0.52 nM) and strong in vitro cell growth inhibition against human cancer cell lines (HCT116 IC50 = 0.098 μM, NCI-N87 IC50 = 0.066 μM) and also displayed high oral bioavailability in mice (F = 44.0%) and potent antitumor efficacy in a human NCI-N87 gastric cancer xenograft model (tumor growth inhibition = 136%). |
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| Keywords: | Structure-based drug design Lead optimization Antitumor agent Hsp90 inhibitor |
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