Design and synthesis of prostate cancer antigen-1 (PCA-1/ALKBH3) inhibitors as anti-prostate cancer drugs |
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| Institution: | 1. Advanced Medical Research Center, Hyogo University of Health Science, 1-3-6 Minatojima, Kobe 650-8530, Japan;2. Department of Pharmacy, Hyogo University of Health Science, 1-3-6 Minatojima, Kobe 650-8530, Japan;3. Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6, Suita 565-0871, Japan;4. Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan;1. Department of Chemistry, Yuvaraja’s College, University of Mysore, Mysore 570 005, India;2. Department of Studies in Chemistry, Manasagangotri, University of Mysore, India;3. Department of Biotechnology, Manasagangotri, University of Mysore, Mysore 570 006, India;1. Department of Chemistry, Faculty of Arts and Sciences, Dumlupinar University, 43100 Kutahya, Turkey;2. Department of Biology, Faculty of Arts and Sciences, Dumlupinar University, 43100 Kutahya, Turkey;3. Department of Physics, Fatih University, 34500 B. Cekmece, Istanbul, Turkey;4. School of Earth Sciences, The Ohio State University, 43210 Columbus, OH, USA;1. Servicio de Cardiología, Hospital Clínico Universitario, INCLIVA, Universitat de València, Valencia, Spain;2. Servicio de Medicina Interna, Hospital de la Plana, Castellón, Spain;3. Servicio de Cardiología, Hospital General Universitario de Valencia, Valencia, Spain;4. Servicio de Medicina Interna, Hospital de Manises, Manises, Valencia, Spain;5. Servicio de Cardiología, Hospital de San Juan, San Juan de Alicante, Alicante, Spain;6. Servicio de Cardiología, Hospital de Manises, Manises, Valencia, Spain;1. Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China;2. Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan 430071, China;3. School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China |
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| Abstract: | A series of 1-aryl-3,4-substituted-1H-pyrazol-5-ol derivatives was synthesized and evaluated as prostate cancer antigen-1 (PCA-1/ALKBH3) inhibitors to obtain a novel anti-prostate cancer drug. After modifying 1-(1H-benzimidazol-2-yl)-3,4-dimethyl-1H-pyrazol-5-ol (1), a hit compound found during random screening using a recombinant PCA-1/ALKBH3, 1-(1H-5-methylbenzimidazol-2-yl)-4-benzyl-3-methyl-1H-pyrazol-5-ol (35, HUHS015), was obtained as a potent PCA-1/ALKBH3 inhibitor both in vitro and in vivo. The bioavailability (BA) of 35 was 7.2% in rats after oral administration. As expected, continuously administering 35 significantly suppressed the growth of DU145 cells, which are human hormone-independent prostate cancer cells, in a mouse xenograft model without untoward effects. |
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| Keywords: | PCA-1 ALKBH3 Inhibitor Anti-prostate cancer drug Small compound Bioavailability |
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