Poster Presentation The 44th Lorne Conference on Protein Structure and Function 2019

Kinetic and crystallographic studies reveal potent new AMPK inhibitor, SBI-0206965, is a highly selective Type IIb kinase inhibitor (#173)

Chris G Langendorf 1 , Toby A Dite 2 , Ashfaqul Hoque 2 , Sandra Galic 1 , Ash J Ovens 1 , Kevin RW Ngoei 1 , Naomi XY Ling 2 , Bruce E Kemp 1 , John W Scott 3 , Jon S Oakhill 2
  1. Protein Chemistry and Metabolism, St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia
  2. Metabolic Signalling Laboratory, St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia
  3. Neurometabolism group, St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia

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. The specificity of SBI-0206965 was tested against a diverse panel of 50 kinases and was compared to that of Compound C. 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 displays preferable characteristics, relative to compound C. Biochemical and structural data provided in this study suggest that SBI-0206965 is a promising lead for the development of a new class of AMPK inhibitors with therapeutic potential.