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


Dite, TA; Langendorf, CG; Hoque, A; Galic, S; Rebello, RJ; Ovens, AJ; Lindqvist, LM; Ngoei, KRW; Ling, NXY; Furic, L; Kemp, BE; Scott, JW; Oakhill, JS
2018-06
2018-04-25
Journal of Biological Chemistry
Journal Article
293
23
8874-8885
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 signalling. Biochemical characterization reveals SBI-0206965 is a mixed type inhibitor. A co-crystal structure of the AMPK kinase domain/SBI-0206965 complex shows 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.
ASBMB
Cell Signalling and Cell Death
10.1074/jbc.RA118.003547
29695504
Refer to copyright notice on published article.

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Creation Date 2018-05-18 09:33:23 Last Modified 2018-10-22 11:36:59