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

Authors :: Machrouhi F
Ouhamou N
Laderoute K
Calaoagan J
Bukhtiyarova M
Ehrlich PJ
Klon AE
Source :: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2010 Nov 15; Vol. 20 (22), pp. 6394-9. Date of Electronic Publication: 2010 Sep 19.
Publication Year :: 2010
Abstract: 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.<br /> (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Subjects :: Drug Design
Humans
Models, Molecular
Phosphorylation
Structure-Activity Relationship
AMP-Activated Protein Kinases antagonists & inhibitors
Protein Kinase Inhibitors chemistry
Protein Kinase Inhibitors pharmacology

Full Text Access

Tools