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），用于指导激酶抑制剂化合物库的构建。对该化合物库开展全激酶组选择性谱分析后，筛选得到一系列4-取代-1H-吡咯并[2,3-b]吡啶类化合物，它们对两类丝裂原活化蛋白激酶（mitogen-activated protein kinases, MAPKs）——TAK1（MAP3K7）与MAP4K2——以及经广泛药理学研究的激酶如p38α（MAPK14）和ABL，均表现出强效抑制活性。后续构效关系（structure–activity relationship, SAR）研究进一步筛选出强效的双靶点TAK1与MAP4K2抑制剂（如化合物1（NG25）、化合物2）以及MAP4K2选择性抑制剂（如化合物16、17）。其中部分化合物具备优良的药代动力学特性，可支持其开展体内药理学研究。TAK1与化合物1的共晶结构分辨率达2.4 Å，该结构证实TAK1的激活环呈现出II型抑制剂标志性的DFG-out构象。