2. Academic Validation
  3. Structure-Based Design of Potent and Selective Inhibitors of the Metabolic Kinase PFKFB3

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

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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