Download MendeleyDiscovery of Type II Inhibitors of TGF beta-Activated Kinase 1 (TAK1) and Mitogen-Activated Protein Kinase Kinase Kinase Kinase 2 (MAP4K2).
Tan, L., Nomanbhoy, T., Gurbani, D., Patricelli, M., Hunter, J., Geng, J., Herhaus, L., Zhang, J., Pauls, E., Ham, Y., Choi, H.G., Xie, T., Deng, X., Buhrlage, S.J., Sim, T., Cohen, P., Sapkota, G., Westover, K.D., Gray, N.S.(2015) J Med Chem 58: 183-196
- PubMed: 25075558
- DOI: https://doi.org/10.1021/jm500480k
- Primary Citation of Related Structures:
4O91 - PubMed Abstract:
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. 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.
Organizational Affiliation:
Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, United States.
