Discovery of Type II Inhibitors of TGFβ-Activated Kinase 1 (TAK1) and Mitogen-Activated Protein Kinase Kinase Kinase Kinase 2 (MAP4K2)

Journal Article · Wed Jul 30 00:00:00 EDT 2014 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/jm500480k· OSTI ID:1179608

Tan, Li ^[1]; Nomanbhoy, Tyzoon ^[2]; Gurbani, Deepak ^[3]; Patricelli, Matthew ^[2]; Hunter, John ^[3]; Geng, Jiefei ^[4]; Herhaus, Lina ^[5]; Zhang, Jianming ^[1]; Pauls, Eduardo ^[5]; Ham, Youngjin ^[1]; Choi, Hwan Geun ^[6]; Xie, Ting ^[1]; Deng, Xianming ^[1]; Buhrlage, Sara J. ^[6]; Sim, Taebo ^[7]; Cohen, Philip ^[5]; Sapkota, Gopal ^[5]; Westover, Kenneth D. ^[3]; Gray, Nathanael S. ^[1]

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1. Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, United States, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States
2. ActivX Biosciences, La Jolla, California 92037, United States
3. Departments of Biochemistry and Radiation Oncology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, United States
4. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, United States
5. MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
6. Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, United States
7. Chemical Kinomics Research Center, Korea Institute of Science and Technology, 39-1, Hawolgok-dong, Seongbuk-gu, Seoul, 136-791, Korea

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.

• Research Organization: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
• Sponsoring Organization: USDOE Office of Science (SC), Biological and Environmental Research (BER)
• Grant/Contract Number: AC02-06CH11357; CA130876-05
• OSTI ID: 1179608
• Alternate ID(s): OSTI ID: 1171855
• Journal Information: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Vol. 58 Journal Issue: 1; ISSN 0022-2623
• Publisher: American Chemical Society
• Country of Publication: United States
• Language: English

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