title: Discovery of type II inhibitors of TGFβ-activated kinase 1 (TAK1) and mitogen-activated protein kinase kinase kinase kinase 2 (MAP4K2).
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.
authors: Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, United States.
authors: Li
authors: L
authors: Tan
authors: Tyzoon
authors: T
authors: Nomanbhoy
authors: Deepak
authors: D
authors: Gurbani
authors: Matthew
authors: M
authors: Patricelli
authors: John
authors: J
authors: Hunter
authors: Jiefei
authors: J
authors: Geng
authors: Lina
authors: L
authors: Herhaus
authors: Jianming
authors: J
authors: Zhang
authors: Eduardo
authors: E
authors: Pauls
authors: Youngjin
authors: Y
authors: Ham
authors: Hwan Geun
authors: HG
authors: Choi
authors: Ting
authors: T
authors: Xie
authors: Xianming
authors: X
authors: Deng
authors: Sara J
authors: SJ
authors: Buhrlage
authors: Taebo
authors: T
authors: Sim
authors: Philip
authors: P
authors: Cohen
authors: Gopal
authors: G
authors: Sapkota
authors: Kenneth D
authors: KD
authors: Westover
authors: Nathanael S
authors: NS
authors: Gray
mesh_terms: D000818:Animals; D019540:Area Under Curve; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015195:Drug Design; D055808:Drug Discovery; D000081410:Germinal Center Kinases; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D008297:Male; D051379:Mice; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D020543:Proteome / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D000081410:Germinal Center Kinases; D020930:MAP Kinase Kinase Kinases; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D020543:Proteome; D011725:Pyridines; D054852:Small Molecule Libraries; D000099151:MAP Kinase Kinase Kinase 7