The rational design of a novel potent analogue of the 5'-AMP-activated protein kinase inhibitor compound C with improved selectivity and cellular activity.

@article{Machrouhi2010TheRD,
  title={The rational design of a novel potent analogue of the 5'-AMP-activated protein kinase inhibitor compound C with improved selectivity and cellular activity.},
  author={Fouzia Machrouhi and Nouara Ouhamou and Keith Laderoute and Joy M Calaoagan and Marina Bukhtiyarova and Paula J Ehrlich and Anthony E. Klon},
  journal={Bioorganic & medicinal chemistry letters},
  year={2010},
  volume={20 22},
  pages={6394-9}
}
We have designed and synthesized analogues of compound C, a non-specific inhibitor of 5'-AMP-activated protein kinase (AMPK), using a computational fragment-based drug design (FBDD) approach. Synthesizing only twenty-seven analogues yielded a compound that was equipotent to compound C in the inhibition of the human AMPK (hAMPK) α2 subunit in the heterotrimeric complex in vitro, exhibited significantly improved selectivity against a subset of relevant kinases, and demonstrated enhanced cellular… CONTINUE READING