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

  • J Med Chem. 2015 Apr 23;58(8):3611-25. doi: 10.1021/acs.jmedchem.5b00352.
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
  • 1. †Oncology Innovative Medicines Unit, AstraZeneca, 35S47 Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
  • 2. ‡CRT Discovery Laboratories, Jonas Webb Building (B910), Babraham Research Campus, Cambridge, CB22 3AT, United Kingdom.
  • 3. §CRT Discovery Laboratories, Wolfson Institute for Biomedical Research, University College London, The Cruciform Building, Gower Street, London WC1E 6BT, United Kingdom.
PMID: 25849762 DOI: 10.1021/acs.jmedchem.5b00352
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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