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Discovery of 2,4-bis-arylamino-1,3-pyrimidines as insulin-like growth factor-1 receptor (IGF-1R) inhibitors |
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| Authors: | Buchanan John L Newcomb John R Carney David P Chaffee Stuart C Chai Lilly Cupples Rod Epstein Linda F Gallant Paul Gu Yan Harmange Jean-Christophe Hodge Kathy Houk Brett E Huang Xin Jona Janan Joseph Smriti Jun H Toni Kumar Rakesh Li Chun Lu John Menges Tom Morrison Michael J Novak Perry M van der Plas Simon Radinsky Robert Rose Paul E Sawant Satin Sun Ji-Rong Surapaneni Sekhar Turci Susan M Xu Keyang Yanez Evelyn Zhao Huilin Zhu Xiaotian |
| Affiliation: | a Department of Medicinal Chemistry, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USA b Department of HTS & Molecular Pharmacology, Amgen Inc., 360 Binney Street, Cambridge, MA 02142 and Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA c Department of Molecular Structure, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USA d Department of Oncology Research, Amgen Inc., 360 Binney Street, Cambridge, MA 02142 and Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA e Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA f Department of Toxicology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA g Department of Pharmaceutics, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA h Department of Metabolic Disorders, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA |
| Abstract: | The insulin-like growth factor-1 receptor (IGF-1R) plays an important role in the regulation of cell growth and differentiation, and in protection from apoptosis. IGF-1R has been shown to be an appealing target for the treatment of human cancer. Herein, we report the synthesis, structure-activity relationships (SAR), X-ray cocrystal structure and in vivo tumor study results for a series of 2,4-bis-arylamino-1,3-pyrimidines. |
| Keywords: | Insulin-like growth factor-1 receptor IGF-1R Kinase Pyrimidine Calu-6 xenograft X-ray cocrystal structure |
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