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AMP-activated Protein Kinase Selectively Inhibited by the Type II Inhibitor SBI-0206965

AMP-activated Protein Kinase Selectively Inhibited by the Type II Inhibitor SBI-0206965

Toby A Dite, Christopher G Langendorf, Ashfaqul Hoque, Sandra Galic, Richard J Rebello, Ashley J Ovens, Lisa M Lindqvist, Kevin R W Ngoei, Naomi X Y Ling, Luc Furic, Bruce E Kemp, John W Scott, Jonathan S Oakhill

J Biol Chem. 2018 Jun 8;293(23):8874-8885.

PMID: 29695504

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4245182	SBI-0206965			Price

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