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.

我们构建了针对II型抑制剂的药效团模型（pharmacophore model），该模型用于指导激酶抑制剂（kinase inhibitors）库的构建。对该抑制剂库开展全激酶组选择性谱分析后，我们筛选得到一系列4位取代的1H-吡咯并[2,3-b]吡啶（4-substituted 1H-pyrrolo[2,3-b]pyridines），这类化合物对两种丝裂原活化蛋白激酶（mitogen-activated protein kinases, MAPKs）——TAK1（MAP3K7）与MAP4K2——以及经药理学充分研究的激酶如p38α（MAPK14）和ABL均表现出强效抑制活性。进一步的构效关系（structure–activity relationship, SAR）研究筛选得到强效的TAK1与MAP4K2双重抑制剂（如化合物1（NG25）和化合物2），以及MAP4K2选择性抑制剂（如化合物16和17）。其中部分抑制剂具备良好的药代动力学特性，可用于体内药理学研究。TAK1与化合物1共晶结构（cocrystal structure）的分辨率达2.4 Å，该结构证实TAK1的激活环（activation loop）呈现出II型抑制剂标志性的DFG-out构象（DFG-out conformation）。