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

Author(s): 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;
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
Research Division(s): Cell Signalling And Cell Death
PubMed ID: 29695504
Publisher's Version: https://doi.org/10.1074/jbc.RA118.003547
Terms of Use/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