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Mechanism and In Vitro Pharmacology of TAK1 Inhibition by (5Z)‑7-Oxozeaenol
journal contribution
posted on 2013-03-15, 00:00 authored by Jiaquan Wu, Francoise Powell, Nicholas
A. Larsen, Zhongwu Lai, Kate F. Byth, Jon Read, Rong-Fang Gu, Mark Roth, Dorin Toader, Jamal Carlos Saeh, Huawei ChenTransforming growth factor-β activated kinase-1
(TAK1) is
a member of the mitogen-activated protein kinase kinase kinase (MAP3K)
family that regulates several signaling pathways including NF-κB
signal transduction and p38 activation. TAK1 deregulation has been
implicated in human diseases including cancer and inflammation. Here,
we show that, in addition to its kinase activity, TAK1 has intrinsic
ATPase activity, that (5Z)-7-Oxozeaenol irreversibly
inhibits TAK1, and that sensitivity to (5Z)-7-Oxozeaenol
inhibition in hematological cancer cell lines is NRAS mutation status
and TAK1 pathway dependent. X-ray crystallographic and mass spectrometric
studies showed that (5Z)-7-Oxozeaenol forms a covalent
complex with TAK1. Detailed biochemical characterization revealed
that (5Z)-7-Oxozeaenol inhibited both the kinase
and the ATPase activity of TAK1 following a bi-phase kinetics, consistent
with the irreversible inhibition mechanism. In DoHH2 cells, (5Z)-7-Oxozeaenol potently inhibited the p38 phosphorylation
driven by TAK1, and the inhibition lasted over 6 h after withdrawal
of (5Z)-7-Oxozeaenol. Profiling (5Z)-7-Oxozeaenol in a panel of hematological cancer cells showed that
sensitive cell lines tended to carry NRAS mutations and that genes
in TAK1 regulated pathways were enriched in sensitive cell lines.
Taken together, we have elucidated the molecular mechanism of a TAK1
irreversible inhibitor and laid the foundation for designing next
generation TAK1 irreversible inhibitors. The NRAS-TAK1-Wnt signaling
network discerned in our study may prove to be useful in patient selection
for TAK1 targeted agents in hematological cancers.