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Azole-based inhibitors of AKT/PKB for the treatment of cancer |
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| Authors: | Qingping Zeng John G Allen Matthew P Bourbeau Xianghong Wang Guomin Yao Seifu Tadesse James T Rider Chester C Yuan Fang-Tsao Hong Matthew R Lee Shiwen Zhang Julie A Lofgren Daniel J Freeman Suijin Yang Chun Li Elizabeth Tominey Xin Huang Douglas Hoffman Harvey K Yamane Christopher Fotsch Xiaoling Zhang |
| Institution: | 1. Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States;2. Oncology Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States;3. Pharmacokinetics and Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States;4. Chemistry Research and Discovery, Amgen, Inc., 360 Binney St., Cambridge, MA 02142, United States;5. Small Molecule Process and Product Development, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States;6. Protein Science, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, United States |
| Abstract: | Through a combination of screening and structure-based rational design, we have discovered a series of N1-(5-(heterocyclyl)-thiazol-2-yl)-3-(4-trifluoromethylphenyl)-1,2-propanediamines that were developed into potent ATP competitive inhibitors of AKT. Studies of linker strand-binding adenine isosteres identified SAR trends in potency and selectivity that were consistent with binding interactions observed in structures of the inhibitors bound to AKT1 and to the counter-screening target PKA. One compound was shown to have acceptable pharmacokinetic properties and to be a potent inhibitor of AKT signaling and of in vivo xenograft tumor growth in a preclinical model of glioblastoma. |
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