The rational design of a novel potent analogue of the 5′-AMP- activated protein kinase inhibitor compound C with improved selectivity and cellular activity
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.
MacHrouhi, Fouzia,Ouhamou, Nouara,Laderoute, Keith,Calaoagan, Joy,Bukhtiyarova, Marina,Ehrlich, Paula J.,Klon, Anthony E.
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p. 6394 - 6399
(2010/12/18)
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