Discovery of potent and selective spiroindolinone MDM2 inhibitor,RO8994, for cancer therapy |
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| Affiliation: | 1. Discovery Chemistry, Roche Research Center, Hoffmann-La Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110, United States;2. Discovery Technologies, Roche Research Center, Hoffmann-La Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110, United States;3. Discovery Oncology, Roche Research Center, Hoffmann-La Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110, United States;4. Non-Clinical Development, Roche Research Center, Hoffmann-La Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110, United States;1. Université Paul Sabatier Toulouse III, UMR 5068, Laboratoire de Synthèse et Physico-Chimie de Molécules d’Intérêt Biologique, 118, Route de Narbonne, F-31062 Toulouse Cedex 9, France;2. CNRS, UMR 5068, Laboratoire de Synthèse et Physico-Chimie de Molécules d’Intérêt Biologique, 118, Route de Narbonne, F-31062 Toulouse Cedex 9, France;3. INSERM, UMR 1048, I2MC, BP 84225, 31432 Toulouse Cedex 4, France;1. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia;2. Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, PO Box 35516, Mansoura, Egypt;3. Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, PO Box 35516, Mansoura, Egypt;4. Department of Pharmacology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia;5. Department of Pharmaceutics and Pharmaceutical Technology (Microbiology), College of Pharmacy, Taibah University, Almadinah Almunawwarah 344, Saudi Arabia;1. Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 1000 Kamoshida-cho, Aoba-ku, Yokohama 227–0033, Japan;2. Sohyaku. Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, 2–2–50 Kawagishi, Toda-shi, Saitama 335–8505, Japan;1. Department of Chemistry, Abdul Wali Khan University, Mardan 23200, Pakistan;2. Department of Biochemistry, Abdul Wali Khan University, Mardan 23200, Pakistan;3. Department of Biochemistry and Biotechnology, The Islamia University of Bahawalpur, Bahawalpur 63100, Pakistan;4. Department of Chemistry, COMSATS Institute of Information Technology, University Road, Abbottabad 22060, Pakistan;5. H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan;1. Key Laboratory of Respiratory Diseases, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190, Kaiyuan Avenue, Science Park, Guangzhou 510530, China;2. Biotechnological Institute of Chinese Materia Medica and Department of Pharmacology, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China |
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| Abstract: | The field of small-molecule inhibitors of protein–protein interactions is rapidly advancing and the specific area of inhibitors of the p53/MDM2 interaction is a prime example. Several groups have published on this topic and multiple compounds are in various stages of clinical development. Building on the strength of the discovery of RG7112, a Nutlin imidazoline-based compound, and RG7388, a pyrrolidine-based compound, we have developed additional scaffolds that provide opportunities for future development. Here, we report the discovery and optimization of a highly potent and selective series of spiroindolinone small-molecule MDM2 inhibitors, culminating in RO8994. |
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| Keywords: | MDM2 p53 Protein–protein interaction Apoptosis Cancer |
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