Machrouhi, F., Ouhamou, N., Laderoute, K., Calaoagan, J., Bukhtiyarova, M., Ehrlich, P. J., & Klon, A. E. (2010). The rational design of a novel potent analogue of the 5′-AMP-activated protein kinase inhibitor compound C with improved selectivity and cellular activity. Bioorganic & medicinal chemistry letters, 20(22), 6394-6399.
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 inhibition of AMPK.