Synthesis of paramagnetic ligands that target the C-terminal binding site of Hsp90 |
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| Affiliation: | 1. Department of Chemistry and Biochemistry, University of Notre Dame, IN, USA;2. Department of Chemistry, University of South Florida, Tampa, FL 33620, USA;1. State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China;2. State Key Laboratory of Chemical Biology and Drug Discovery, and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Kowloon, Hong Kong;3. Division of Molecular Therapeutics & Formulation, School of Pharmacy, The University of Nottingham, University Park Campus, Nottingham NG7 2RD, UK;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. Department of Surgery, University of Michigan, Ann Arbor, MI;2. Department of Pharmacology, University of Michigan, Ann Arbor, MI;3. Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN;4. Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI |
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| Abstract: | Identification of a ligand binding site represents the starting point for a structure-based drug development program. Lack of a binding site hampers the development of improved ligands that modulate the protein of interest. In this letter, we describe the development of chemical tools that will allow for elucidation of the Hsp90 C-terminal ligand binding site. Our strategy is based on the preparation of paramagnetic analogs of KU-596, an investigational new drug that is currently undergoing clinical trials for the treatment of neuropathy and interacts with the Hsp90 C-terminal domain. In particular, we report the design and synthesis of three novel paramagnetic analogs of KU-596, which will be used to obtain long range distances for NMR structural studies of Hsp90 in complex with C-terminal ligands. |
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| Keywords: | Paramagnetic ligand HSP90 C-terminal KU-596 ESR |
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