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Liang, Yanke

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Liang

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Yanke

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Liang, Yanke

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20142

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Author's Publications: search.filters.isAuthorOfPublication.f270f82e-aada-42be-9a8a-2a4a55dd3897

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    A unique inhibitor binding site in ERK1/2 is associated with slow binding kinetics
    (2014) Chaikuad, Apirat; Tacconi, Eliana; Zimmer, Jutta; Liang, Yanke; Gray, Nathanael; Tarsounas, Madalena; Knapp, Stefan
    Activation of the ERK pathway is a hallmark of cancer and targeting of upstream signalling partners led to the development of approved drugs. Recently SCH772984 has been shown to be a selective and potent ERK1/2 inhibitor. Here we report the structural mechanism for its remarkable selectivity. In ERK1/2, SCH772984 induced a so far unknown binding pocket that accommodated the piperazine-phenyl-pyrimidine decoration. This novel binding pocket was created by an inactive conformation of the phosphate binding loop and an outward tilt of helix αC. In contrast, structure determination of SCH772984 with the off-target haspin and JNK1 revealed canonical but two distinct type-I binding modes. Intriguingly, the novel binding mode with ERK1/2 was associated with slow binding kinetics in vitro as well as in cell based assay systems. The described binding mode of SCH772984 with ERK1/2 enables the design of a new type of specific kinase inhibitors with prolonged on-target activity.
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    Discovery of a Potent, Covalent BTK Inhibitor for B-Cell Lymphoma
    (American Chemical Society, 2014) Wu, Hong; Wang, Wenchao; Liu, Feiyang; Weisberg, Ellen; Tian, Bei; Chen, Yongfei; Li, Binhua; Wang, Aoli; Wang, Beilei; Zhao, Zheng; McMillin, Douglas W.; Hu, Chen; Li, Hong; Wang, Jinhua; Liang, Yanke; Buhrlage, Sara J.; Liang, Junting; Liu, Jing; Yang, Guang; Brown, Jennifer R.; Treon, Steven; Mitsiades, Constantine; Griffin, James; Liu, Qingsong; Gray, Nathanael
    BTK is a member of the TEC family of non-receptor tyrosine kinases whose deregulation has been implicated in a variety of B-cell-related diseases. We have used structure-based drug design in conjunction with kinome profiling and cellular assays to develop a potent, selective, and irreversible BTK kinase inhibitor, QL47, which covalently modifies Cys481. QL47 inhibits BTK kinase activity with an IC50 of 7 nM, inhibits autophosphorylation of BTK on Tyr223 in cells with an EC50 of 475 nM, and inhibits phosphorylation of a downstream effector PLCγ2 (Tyr759) with an EC50 of 318 nM. In Ramos cells QL47 induces a G1 cell cycle arrest that is associated with pronounced degradation of BTK protein. QL47 inhibits the proliferation of B-cell lymphoma cancer cell lines at submicromolar concentrations.