Discovery of type II inhibitors of tgfβ-activated kinase 1 (TAK1) and mitogen-activated protein kinase kinase kinase kinase 2 (MAP4K2)

TY - JOUR

T1 - Discovery of type II inhibitors of tgfβ-activated kinase 1 (TAK1) and mitogen-activated protein kinase kinase kinase kinase 2 (MAP4K2)

AU - Tan, Li

AU - Nomanbhoy, Tyzoon

AU - Gurbani, Deepak

AU - Patricelli, Matthew

AU - Hunter, John

AU - Geng, Jiefei

AU - Herhaus, Lina

AU - Zhang, Jianming

AU - Pauls, Eduardo

AU - Ham, Youngjin

AU - Choi, Hwan Geun

AU - Xie, Ting

AU - Deng, Xianming

AU - Buhrlage, Sara J.

AU - Sim, Taebo

AU - Cohen, Philip

AU - Sapkota, Gopal

AU - Westover, Kenneth D.

AU - Gray, Nathanael S.

PY - 2015/1/8

Y1 - 2015/1/8

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84920827062

U2 - 10.1021/jm500480k

DO - 10.1021/jm500480k

M3 - Article

C2 - 25075558

AN - SCOPUS:84920827062

SN - 0022-2623

VL - 58

SP - 183

EP - 196

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 1

ER -