Discovery of Type II Inhibitors of TGFβ-Activated Kinase 1 (TAK1) and Mitogen-Activated Protein Kinase Kinase Kinase Kinase 2 (MAP4K2) [electronic resource].
- Washington, D.C. : United States. Dept. of Energy. Office of Science, 2014. and Oak Ridge, Tenn. : Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy
- Physical Description:
- pages 183-196 : digital, PDF file
- Additional Creators:
- Argonne National Laboratory, United States. Department of Energy. Office of Science, and United States. Department of Energy. Office of Scientific and Technical Information
- Here, we developed a pharmacophore model for type II inhibitors that was used to guide the construction of a library of kinase inhibitors. Kinome-wide selectivity profiling of the library resulted in the identification of a series of 4-substituted 1H-pyrrolo[2,3-b]pyridines that exhibited potent inhibitory activity against two mitogen-activated protein kinases (MAPKs), TAK1 (MAP3K7) and MAP4K2, as well as pharmacologically well interrogated kinases such as p38α (MAPK14) and ABL. Further investigation of the structure–activity relationship (SAR) resulted in the identification of potent dual TAK1 and MAP4K2 inhibitors such as 1 (NG25) and 2 as well as MAP4K2 selective inhibitors such as 16 and 17. Some of these inhibitors possess good pharmacokinetic properties that will enable their use in pharmacological studies in vivo. Lastly, a 2.4 Å cocrystal structure of TAK1 in complex with 1 confirms that the activation loop of TAK1 assumes the DFG-out conformation characteristic of type II inhibitors.
- Published through SciTech Connect., 07/17/2014., Journal of Medicinal Chemistry 58 1 ISSN 0022-2623 AM, and Li Tan; Tyzoon Nomanbhoy; Deepak Gurbani; Matthew Patricelli; John Hunter; Jiefei Geng; Lina Herhaus; Jianming Zhang; Eduardo Pauls; Youngjin Ham; Hwan Geun Choi; Ting Xie; Xianming Deng; Sara J. Buhrlage; Taebo Sim; Philip Cohen; Gopal Sapkota; Kenneth D. Westover; Nathanael S. Gray.
- Funding Information:
- AC02-06CH11357 and CA130876-05
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