posted on 2015-04-23, 00:00authored byScott 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.