Structure-assisted discovery of the first non-retinoid ligands for Retinol-Binding Protein 4 |
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| Institution: | 1. Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA;2. Department of Metabolic Disorders, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA;3. Department of Pharmacokinetics & Drug Metabolism, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA;1. GlaxoSmithKline, Antiviral Discovery Performance Unit, 5 Moore Drive, Research Triangle Park, NC 27709, USA;2. GlaxoSmithKline, Platform Technology and Science, 5 Moore Drive, Research Triangle Park, NC 27709, USA;3. GlaxoSmithKline, Anti Bacterial Discovery Performance Unit, 5 Moore Drive, Research Triangle Park, NC 27709, USA;1. Imperial College Genetic Therapies Centre, Department of Chemistry, Flowers Building, Armstrong Road, Imperial College London, London SW7 2AZ,UK;2. Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad, India;3. Institute of Pharmaceutical Science, King’s College London, Franklin-Wilkins Building, Waterloo Campus, 150 Stamford Street, London SE1 9NH,UK;4. Institute of Biomedical Engineering, Armstrong Road, Imperial College London, London SW7 2AZ,UK;1. Medicinal Chemistry Department, Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada;2. Biology Department, Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada;1. Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA;2. Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA;3. Department of Therapeutic Discovery, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USA;4. Department of Oncology Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA |
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| Abstract: | Retinol-Binding Protein 4 (RBP4) is a plasma protein that transports retinol (vitamin A) from the liver to peripheral tissues. This Letter highlights our efforts in discovering the first, to our knowledge, non-retinoid small molecules that bind to RBP4 at the retinol site and reduce serum RBP4 levels in mice, by disrupting the interaction between RBP4 and transthyretin (TTR), a plasma protein that binds RBP4 and protects it from renal excretion. Potent compounds were discovered and optimized quickly from high-throughput screen (HTS) hits utilizing a structure-based approach. Inhibitor co-crystal X-ray structures revealed unique disruptions of RBP4–TTR interactions by our compounds through induced loop conformational changes instead of steric hindrance exemplified by fenretinide. When administered to mice, A1120, a representative compound in the series, showed concentration-dependent retinol and RBP4 lowering. |
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| Keywords: | RBP4 A1120 Non-retinoid Small molecules Fenretinide |
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