Signal Transduction
AMP-activated protein kinase selectively inhibited by the type II inhibitor SBI-0206965

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Inhibition of the metabolic regulator AMP-activated protein kinase (AMPK) is increasingly being investigated for its therapeutic potential in diseases where AMPK hyperactivity results in poor prognoses, as in established cancers and neurodegeneration. However, AMPK-inhibitory tool compounds are largely limited to compound C, which has a poor selectivity profile. Here we identify the pyrimidine derivative SBI-0206965 as a direct AMPK inhibitor. SBI-0206965 inhibits AMPK with 40-fold greater potency and markedly lower kinase promiscuity than compound C and inhibits cellular AMPK signaling. Biochemical characterization reveals that SBI-0206965 is a mixed-type inhibitor. A co-crystal structure of the AMPK kinase domain/SBI-0206965 complex shows that the drug occupies a pocket that partially overlaps the ATP active site in a type IIb inhibitor manner. SBI-0206965 has utility as a tool compound for investigating physiological roles for AMPK and provides fresh impetus to small-molecule AMPK inhibitor therapeutic development.

AMP-activated kinase (AMPK)
cell metabolism
drug development
inhibition mechanism
signaling
structure-function
appetite suppression
neuroprotection

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This work was supported by grants from the Australian Research Council (ARC), Cancer Australia, the National Health and Medical Research Council (NHMRC), and the Jack Brockhoff foundation (Grant JBF-4206, 2016). The authors declare that they have no conflicts of interest with the contents of this article.

This article contains Table S1 and Figs. S1–S4.

The atomic coordinates and structure factors (code 6BX6) have been deposited in the Protein Data Bank (http://wwpdb.org/).

1

An NHMRC Early Career Research Fellow. Supported in part by the Victorian Government's Operational Infrastructure Support Program.

2

Supported by the Department of Health and Human Services acting through the Victorian Cancer Agency (MCRF16007).

3

An NHMRC Research Fellow.