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

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2018 Apr 27

PMID 29695504

Citations 59

Authors

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

Affiliations

Soon will be listed here.

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.

Citing Articles

Measuring Cellular Adenine Nucleotides by Liquid Chromatography-Coupled Mass Spectrometry.

Ovens A, Yu D, Dite T, Kemp B, Oakhill J Methods Mol Biol. 2025; 2882:3-14.

PMID: 39992502 DOI: 10.1007/978-1-0716-4284-9_1.

Small Molecule Modulators of AMP-Activated Protein Kinase (AMPK) Activity and Their Potential in Cancer Therapy.

Strang J, Astridge D, Nguyen V, Reigan P J Med Chem. 2025; 68(3):2238-2254.

PMID: 39879193 PMC: 11831681. DOI: 10.1021/acs.jmedchem.4c02354.

The anti-senescence effect of D-β-hydroxybutyrate in Hutchinson-Gilford progeria syndrome involves progerin clearance by the activation of the AMPK-mTOR-autophagy pathway.

Monterrubio-Ledezma F, Salcido-Gomez A, Zavaleta-Vasquez T, Navarro-Garcia F, Cisneros B, Massieu L Geroscience. 2025; .

PMID: 39821043 DOI: 10.1007/s11357-024-01501-9.

Targeting protein synthesis pathways in MYC-amplified medulloblastoma.

Kumar D, Kanchan R, Chaturvedi N Discov Oncol. 2025; 16(1):23.

PMID: 39779613 PMC: 11711608. DOI: 10.1007/s12672-025-01761-7.

Hypoglycaemic stimulation of macrophage cytokine release is suppressed by AMP-activated protein kinase activation.

Zhang J, Pollard A, Pearson E, Carling D, Viollet B, Ellacott K Diabet Med. 2024; 42(3):e15456.

PMID: 39717018 PMC: 11823358. DOI: 10.1111/dme.15456.

References

Cokorinos E, Delmore J, Reyes A, Albuquerque B, Kjobsted R, Jorgensen N . Activation of Skeletal Muscle AMPK Promotes Glucose Disposal and Glucose Lowering in Non-human Primates and Mice. Cell Metab. 2017; 25(5):1147-1159.e10. DOI: 10.1016/j.cmet.2017.04.010. View

Kovalenko M, Ronnstrand L, Heldin C, Loubtchenkov M, Gazit A, Levitzki A . Phosphorylation site-specific inhibition of platelet-derived growth factor beta-receptor autophosphorylation by the receptor blocking tyrphostin AG1296. Biochemistry. 1997; 36(21):6260-9. DOI: 10.1021/bi962553l. View

Davidson W, Frego L, Peet G, Kroe R, Labadia M, Lukas S . Discovery and characterization of a substrate selective p38alpha inhibitor. Biochemistry. 2004; 43(37):11658-71. DOI: 10.1021/bi0495073. View

Liu Y, Chern Y . AMPK-mediated regulation of neuronal metabolism and function in brain diseases. J Neurogenet. 2015; 29(2-3):50-8. DOI: 10.3109/01677063.2015.1067203. View

Emsley P, Lohkamp B, Scott W, Cowtan K . Features and development of Coot. Acta Crystallogr D Biol Crystallogr. 2010; 66(Pt 4):486-501. PMC: 2852313. DOI: 10.1107/S0907444910007493. View

Schuttelkopf A, van Aalten D . PRODRG: a tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr D Biol Crystallogr. 2004; 60(Pt 8):1355-63. DOI: 10.1107/S0907444904011679. View

Evans P, Murshudov G . How good are my data and what is the resolution?. Acta Crystallogr D Biol Crystallogr. 2013; 69(Pt 7):1204-14. PMC: 3689523. DOI: 10.1107/S0907444913000061. View

Handa N, Takagi T, Saijo S, Kishishita S, Takaya D, Toyama M . Structural basis for compound C inhibition of the human AMP-activated protein kinase α2 subunit kinase domain. Acta Crystallogr D Biol Crystallogr. 2011; 67(Pt 5):480-7. DOI: 10.1107/S0907444911010201. View

Langendorf C, Ngoei K, Scott J, Ling N, Issa S, Gorman M . Structural basis of allosteric and synergistic activation of AMPK by furan-2-phosphonic derivative C2 binding. Nat Commun. 2016; 7:10912. PMC: 4786773. DOI: 10.1038/ncomms10912. View

10.

Vijayan R, He P, Modi V, Duong-Ly K, Ma H, Peterson J . Conformational analysis of the DFG-out kinase motif and biochemical profiling of structurally validated type II inhibitors. J Med Chem. 2014; 58(1):466-79. PMC: 4326797. DOI: 10.1021/jm501603h. View

11.

McCoy A, Grosse-Kunstleve R, Adams P, Winn M, Storoni L, Read R . Phaser crystallographic software. J Appl Crystallogr. 2009; 40(Pt 4):658-674. PMC: 2483472. DOI: 10.1107/S0021889807021206. View

12.

Chen V, Arendall 3rd W, Headd J, Keedy D, Immormino R, Kapral G . MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr D Biol Crystallogr. 2010; 66(Pt 1):12-21. PMC: 2803126. DOI: 10.1107/S0907444909042073. View

13.

Grahame Hardie D, Schaffer B, Brunet A . AMPK: An Energy-Sensing Pathway with Multiple Inputs and Outputs. Trends Cell Biol. 2015; 26(3):190-201. PMC: 5881568. DOI: 10.1016/j.tcb.2015.10.013. View

14.

Ross F, Jensen T, Grahame Hardie D . Differential regulation by AMP and ADP of AMPK complexes containing different γ subunit isoforms. Biochem J. 2015; 473(2):189-99. PMC: 4700476. DOI: 10.1042/BJ20150910. View

15.

Jeon S, Hay N . The double-edged sword of AMPK signaling in cancer and its therapeutic implications. Arch Pharm Res. 2015; 38(3):346-57. PMC: 5789788. DOI: 10.1007/s12272-015-0549-z. View

16.

Ghani U, Ullah N . New potent inhibitors of tyrosinase: novel clues to binding of 1,3,4-thiadiazole-2(3H)-thiones, 1,3,4-oxadiazole-2(3H)-thiones, 4-amino-1,2,4-triazole-5(4H)-thiones, and substituted hydrazides to the dicopper active site. Bioorg Med Chem. 2010; 18(11):4042-8. DOI: 10.1016/j.bmc.2010.04.021. View

17.

Dite T, Ling N, Scott J, Hoque A, Galic S, Parker B . The autophagy initiator ULK1 sensitizes AMPK to allosteric drugs. Nat Commun. 2017; 8(1):571. PMC: 5603566. DOI: 10.1038/s41467-017-00628-y. View

18.

Afonine P, Grosse-Kunstleve R, Echols N, Headd J, Moriarty N, Mustyakimov M . Towards automated crystallographic structure refinement with phenix.refine. Acta Crystallogr D Biol Crystallogr. 2012; 68(Pt 4):352-67. PMC: 3322595. DOI: 10.1107/S0907444912001308. View

19.

Nam M, Lee W, Bae E, Kim S . Compound C inhibits clonal expansion of preadipocytes by increasing p21 level irrespectively of AMPK inhibition. Arch Biochem Biophys. 2008; 479(1):74-81. DOI: 10.1016/j.abb.2008.07.029. View

20.

Zheng J, Trafny E, Knighton D, Xuong N, Taylor S, Ten Eyck L . 2.2 A refined crystal structure of the catalytic subunit of cAMP-dependent protein kinase complexed with MnATP and a peptide inhibitor. Acta Crystallogr D Biol Crystallogr. 1993; 49(Pt 3):362-5. DOI: 10.1107/S0907444993000423. View