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. 2015 Apr 23;58(8):3611-25.
doi: 10.1021/acs.jmedchem.5b00352. Epub 2015 Apr 13.

Structure-Based Design of Potent and Selective Inhibitors of the Metabolic Kinase PFKFB3

Scott Boyd  1 , Joanna L Brookfield  2 , Susan E Critchlow  1 , Iain A Cumming  2 , Nicola J Curtis  1 , Judit Debreczeni  1 , Sébastien L Degorce  1 , Craig Donald  1 , Nicola J Evans  3 , Sam Groombridge  1 , Philip Hopcroft  1 , Neil P Jones  3 , Jason G Kettle  1 , Scott Lamont  1 , Hilary J Lewis  1 , Philip MacFaull  1 , Sheila B McLoughlin  2 , Laurent J M Rigoreau  2 , James M Smith  2 , Steve St-Gallay  1 , Julie K Stock  3 , Andrew P Turnbull  3 , Edward R Wheatley  3 , Jon Winter  1 , Jonathan Wingfield  1
Affiliations

Structure-Based Design of Potent and Selective Inhibitors of the Metabolic Kinase PFKFB3

Scott Boyd et al. J Med Chem. .

Abstract

A weak screening hit with suboptimal physicochemical properties was optimized against PFKFB3 kinase using critical structure-guided insights. The resulting compounds demonstrated high selectivity over related PFKFB isoforms and modulation of the target in a cellular context. A selected example demonstrated exposure in animals following oral dosing. Examples from this series may serve as useful probes to understand the emerging biology of this metabolic target.

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