Title: AMP-activated protein kinase selectively inhibited by the type II inhibitor SBI-0206965
Authors: 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
Issue Year: 2018
Publisher AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Series J. Biol. Chem.:
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 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.
URI: https://publications.svi.edu.au/publications/4470
Other Identifiers 10.1074/jbc.RA118.003547
Publication type Article