2. Academic Validation
  3. Discovery of type II inhibitors of TGFβ-activated kinase 1 (TAK1) and mitogen-activated protein kinase kinase kinase kinase 2 (MAP4K2)

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

  • J Med Chem. 2015 Jan 8;58(1):183-96. doi: 10.1021/jm500480k.
Li Tan 1,  Tyzoon Nomanbhoy,  Deepak Gurbani,  Matthew Patricelli,  John Hunter,  Jiefei Geng,  Lina Herhaus,  Jianming Zhang,  Eduardo Pauls,  Youngjin Ham,  Hwan Geun Choi,  Ting Xie,  Xianming Deng,  Sara J Buhrlage,  Taebo Sim,  Philip Cohen,  Gopal Sapkota,  Kenneth D Westover,  Nathanael S Gray
Affiliations

Affiliation

  • 1 Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, United States.
PMID: 25075558 DOI: 10.1021/jm500480k
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.

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