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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)

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. Harvard Medical School, Boston, MA (United States). Dana Farber Cancer Inst., Dept. of Biological Chemistry and Molecular Pharmacology
  2. ActivX Biosciences, La Jolla, CA (United States)
  3. Univ. of Texas Southwestern Medical Center, Dallas, TX (United States). Dept. of Biochemistry and Radiation Oncology
  4. Harvard Medical School, Boston, MA (United States). Dept. of Cell Biology
  5. Univ. of Dundee (United Kingdom). College of Life Sciences
  6. Harvard Medical School, Boston, MA (United States). Dana Farber Cancer Inst.
  7. Korea Inst. of Science and Technology, Seoul (Korea). Chemical Kinomics Research Center
Publication Date:
OSTI Identifier:
1179608
Grant/Contract Number:
AC02-06CH11357; CA130876-05
Type:
Published Article
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 58; Journal Issue: 1; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Research Org:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 60 APPLIED LIFE SCIENCES