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Aminoindazole PDK1 Inhibitors: A Case Study in Fragment-Based Drug Discovery.

ABSTRACT: Fragment screening of phosphoinositide-dependent kinase-1 (PDK1) in a biochemical kinase assay afforded hits that were characterized and prioritized based on ligand efficiency and binding interactions with PDK1 as determined by NMR. Subsequent crystallography and follow-up screening led to the discovery of aminoindazole 19, a potent leadlike PDK1 inhibitor with high ligand efficiency. Well-defined structure-activity relationships and protein crystallography provide a basis for further elaboration and optimization of 19 as a PDK1 inhibitor.

SUBMITTER: Medina JR 

PROVIDER: S-EPMC4007849 | biostudies-other | 2010 Nov

REPOSITORIES: biostudies-other

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Aminoindazole PDK1 Inhibitors: A Case Study in Fragment-Based Drug Discovery.

Medina Jesús R JR   Blackledge Charles W CW   Heerding Dirk A DA   Campobasso Nino N   Ward Paris P   Briand Jacques J   Wright Lois L   Axten Jeffrey M JM  

ACS medicinal chemistry letters 20100722 8

Fragment screening of phosphoinositide-dependent kinase-1 (PDK1) in a biochemical kinase assay afforded hits that were characterized and prioritized based on ligand efficiency and binding interactions with PDK1 as determined by NMR. Subsequent crystallography and follow-up screening led to the discovery of aminoindazole 19, a potent leadlike PDK1 inhibitor with high ligand efficiency. Well-defined structure-activity relationships and protein crystallography provide a basis for further elaboratio  ...[more]