AMP-activated protein kinase selectively inhibited by the type II inhibitor SBI-0206965
Details
Publication Year 2018-06, Volume 293, Issue #23, Page 8874-8885
Journal Title
Journal of Biological Chemistry
Publication Type
Journal Article
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 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.
Publisher
ASBMB
WEHI Research Division(s)
Cell Signalling And Cell Death
PubMed ID
29695504
Rights Notice
Refer to copyright notice on published article.


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