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Discovery of novel phenoxybenzamide analogues as Raf/HDAC dual inhibitors
Institution:1. Department of Organic Chemistry, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China;2. Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China;3. State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China;4. Shanxi Key Laboratory of Natural Products & Chemical Biology, College of Science, Northwest A&F University, Yangling 712100, China;1. Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland;2. Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland;1. Department of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, PR China;2. School of Pharmacy, Health Science Center, Xi’an Jiaotong University, Xi’an, Shaanxi Province, PR China;1. Department of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries Research, National Research Centre, Dokki, Cairo, Egypt;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt;3. Molecular Modeling Unit, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt;4. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, New Giza University, New Giza, km 22 Cairo–Alexandria Desert Road, Cairo, Egypt;5. Department of Biochemistry, Division of Genetic Engineering and Biotechnology, National Research Centre, Cairo, Egypt;1. Normandie Univ, UNIROUEN, INSA Rouen, CNRS, COBRA (UMR 6014), 76000, Rouen, France;2. Institut de Biologie Structurale, Université Grenoble Alpes, Centre National de la Recherche Scientifique (CNRS)-Commissariat à l’Énergie Atomique (CEA) (UMR 5075), F-38054, Grenoble, France;3. Institut Laue Langevin, 71, avenue des Martyrs - CS 20156, 38042, Grenoble cedex 9, France;4. Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Via Belmeloro 6, I-40126, Bologna, Italy;5. Plateforme ImPACcell-SFR BIOSIT UMS-CNRS3480 UMS-INSERM018, Université de Rennes1, 35043, Rennes Cedex, France;6. Sorbonne Université, CNRS USR 3151, Protein Phosphorylation & Human Diseases, Station Biologique de Roscoff, CS 90074, Roscoff Cedex, F-29688, France;7. Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari “Aldo Moro”, via Edoardo Orabona 4, 70125, Bari, Italy;8. Istituto Tumori IRCCS Giovanni Paolo II, via le Orazio Flacco 65, 70124, Bari, Italy;9. Department of Neurobiology, Weizmann Institute of Science, 6100, Rehovot, Israel;10. Department of Structural Biology, Weizmann Institute of Science, 76100, Rehovot, Israel;11. Institut de Chimie Organique et Analytique, Université d’Orléans, UMR CNRS 7311, rue de Chartres, BP 6759, 45067, Orléans Cedex 2, France;1. Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, PR China;2. Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China
Abstract:Histone deacetylase (HDAC) inhibitors as an important epigenetic therapeutic strategy affect signaling networks and act synergistically with kinase inhibitors for the treatment of cancer. Herein we presented a series of novel phenoxybenzamide analogues with inhibition of Raf and HDAC. Among them, compound 10e showed potent antiproliferative activities against Hepg2 and MDA-MB-468 in cellular assays. This work may lay the foundation for developing novel dual Raf/HDAC inhibitors as potential anticancer therapeutics.
Keywords:Raf  HDAC  Dual inhibitor  Antiproliferative activity  Phenoxybenzamide
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