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

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

doi:10.1021/acs.jmedchem.5b00352.s001

jm5b00352_si_001.pdf (502.91 kB)

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

journal contribution

posted on 2015-04-23, 00:00 authored by Scott Boyd, Joanna L. Brookfield, Susan E. Critchlow, Iain A. Cumming, Nicola J. Curtis, Judit Debreczeni, Sébastien L. Degorce, Craig Donald, Nicola J. Evans, Sam Groombridge, Philip Hopcroft, Neil P. Jones, Jason G. Kettle, Scott Lamont, Hilary J. Lewis, Philip MacFaull, Sheila B. McLoughlin, Laurent J. M. Rigoreau, James M. Smith, Steve St-Gallay, Julie K. Stock, Andrew P. Turnbull, Edward R. Wheatley, Jon Winter, Jonathan Wingfield

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.