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

Title
Discovery of Type II Inhibitors of TGFβ-Activated Kinase 1 (TAK1) and Mitogen-Activated Protein Kinase Kinase Kinase Kinase 2 (MAP4K2)
Authors
Li TanTyzoon NomanbhoyDeepak GurbaniMatthew PatricelliJohn HunterJiefei GengLina HerhausJianming ZhangEduardo PaulsYoungjin HamHwan Geun ChoiTing XieXianming DengSara J. Buhrlage심태보Philip CohenGopal SapkotaKenneth D. WestoverNathanael S. Gray
Keywords
TAK1
Issue Date
2015-01
Publisher
Journal of medicinal chemistry
Citation
VOL 58, NO S1, 183-196
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 p38a (MAPK14) and ABL. Further investigation of the structureactivity 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 angstrom 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.
URI
http://pubs.kist.re.kr/handle/201004/50840
ISSN
00222623
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KIST Publication > Article
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