Journal article
AMP-activated protein kinase selectively inhibited by the type II inhibitor SBI-0206965
TA Dite, CG Langendorf, A Hoque, S Galic, RJ Rebello, AJ Ovens, LM Lindqvist, KRW Ngoei, NXY Ling, L Furic, BE Kemp, JW Scott, JS Oakhill
Journal of Biological Chemistry | AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC | Published : 2018
Open access
Abstract
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 o..
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Awarded by Australian Research Council
Funding Acknowledgements
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.An NHMRC Early Career Research Fellow. Supported in part by the Victorian Government's Operational Infrastructure Support Program.Supported by the Department of Health and Human Services acting through the Victorian Cancer Agency (MCRF16007).