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

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.