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

Abstract

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.

Authors:
 [1];  [2];  [3];  [2];  [3];  [4];  [5];  [1];  [5];  [1];  [6];  [1];  [1];  [6];  [7];  [5];  [5];  [3];  [1]
  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
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER)
OSTI Identifier:
1179608
Alternate Identifier(s):
OSTI ID: 1171855
Grant/Contract Number:  
AC02-06CH11357; CA130876-05
Resource Type:
Published Article
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Name: Journal of Medicinal Chemistry Journal Volume: 58 Journal Issue: 1; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 60 APPLIED LIFE SCIENCES

Citation Formats

Tan, Li, Nomanbhoy, Tyzoon, Gurbani, Deepak, Patricelli, Matthew, Hunter, John, Geng, Jiefei, Herhaus, Lina, Zhang, Jianming, Pauls, Eduardo, Ham, Youngjin, Choi, Hwan Geun, Xie, Ting, Deng, Xianming, Buhrlage, Sara J., Sim, Taebo, Cohen, Philip, Sapkota, Gopal, Westover, Kenneth D., and Gray, Nathanael S. Discovery of Type II Inhibitors of TGFβ-Activated Kinase 1 (TAK1) and Mitogen-Activated Protein Kinase Kinase Kinase Kinase 2 (MAP4K2). United States: N. p., 2014. Web. doi:10.1021/jm500480k.
Tan, Li, Nomanbhoy, Tyzoon, Gurbani, Deepak, Patricelli, Matthew, Hunter, John, Geng, Jiefei, Herhaus, Lina, Zhang, Jianming, Pauls, Eduardo, Ham, Youngjin, Choi, Hwan Geun, Xie, Ting, Deng, Xianming, Buhrlage, Sara J., Sim, Taebo, Cohen, Philip, Sapkota, Gopal, Westover, Kenneth D., & Gray, Nathanael S. Discovery of Type II Inhibitors of TGFβ-Activated Kinase 1 (TAK1) and Mitogen-Activated Protein Kinase Kinase Kinase Kinase 2 (MAP4K2). United States. https://doi.org/10.1021/jm500480k
Tan, Li, Nomanbhoy, Tyzoon, Gurbani, Deepak, Patricelli, Matthew, Hunter, John, Geng, Jiefei, Herhaus, Lina, Zhang, Jianming, Pauls, Eduardo, Ham, Youngjin, Choi, Hwan Geun, Xie, Ting, Deng, Xianming, Buhrlage, Sara J., Sim, Taebo, Cohen, Philip, Sapkota, Gopal, Westover, Kenneth D., and Gray, Nathanael S. Wed . "Discovery of Type II Inhibitors of TGFβ-Activated Kinase 1 (TAK1) and Mitogen-Activated Protein Kinase Kinase Kinase Kinase 2 (MAP4K2)". United States. https://doi.org/10.1021/jm500480k.
@article{osti_1179608,
title = {Discovery of Type II Inhibitors of TGFβ-Activated Kinase 1 (TAK1) and Mitogen-Activated Protein Kinase Kinase Kinase Kinase 2 (MAP4K2)},
author = {Tan, Li and Nomanbhoy, Tyzoon and Gurbani, Deepak and Patricelli, Matthew and Hunter, John and Geng, Jiefei and Herhaus, Lina and Zhang, Jianming and Pauls, Eduardo and Ham, Youngjin and Choi, Hwan Geun and Xie, Ting and Deng, Xianming and Buhrlage, Sara J. and Sim, Taebo and Cohen, Philip and Sapkota, Gopal and Westover, Kenneth D. and Gray, Nathanael S.},
abstractNote = {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.},
doi = {10.1021/jm500480k},
journal = {Journal of Medicinal Chemistry},
number = 1,
volume = 58,
place = {United States},
year = {Wed Jul 30 00:00:00 EDT 2014},
month = {Wed Jul 30 00:00:00 EDT 2014}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
https://doi.org/10.1021/jm500480k

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