title: Structure-Based Design of Potent and Selective Inhibitors of the Metabolic Kinase PFKFB3.
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.
authors: †Oncology Innovative Medicines Unit, AstraZeneca, 35S47 Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors: Scott
authors: S
authors: Boyd
authors: ‡CRT Discovery Laboratories, Jonas Webb Building (B910), Babraham Research Campus, Cambridge, CB22 3AT, United Kingdom.
authors: Joanna L
authors: JL
authors: Brookfield
authors: †Oncology Innovative Medicines Unit, AstraZeneca, 35S47 Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors: Susan E
authors: SE
authors: Critchlow
authors: ‡CRT Discovery Laboratories, Jonas Webb Building (B910), Babraham Research Campus, Cambridge, CB22 3AT, United Kingdom.
authors: Iain A
authors: IA
authors: Cumming
authors: †Oncology Innovative Medicines Unit, AstraZeneca, 35S47 Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors: Nicola J
authors: NJ
authors: Curtis
authors: †Oncology Innovative Medicines Unit, AstraZeneca, 35S47 Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors: Judit
authors: J
authors: Debreczeni
authors: †Oncology Innovative Medicines Unit, AstraZeneca, 35S47 Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors: Sébastien L
authors: SL
authors: Degorce
authors: †Oncology Innovative Medicines Unit, AstraZeneca, 35S47 Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors: Craig
authors: C
authors: Donald
authors: §CRT Discovery Laboratories, Wolfson Institute for Biomedical Research, University College London, The Cruciform Building, Gower Street, London WC1E 6BT, United Kingdom.
authors: Nicola J
authors: NJ
authors: Evans
authors: †Oncology Innovative Medicines Unit, AstraZeneca, 35S47 Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors: Sam
authors: S
authors: Groombridge
authors: †Oncology Innovative Medicines Unit, AstraZeneca, 35S47 Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors: Philip
authors: P
authors: Hopcroft
authors: §CRT Discovery Laboratories, Wolfson Institute for Biomedical Research, University College London, The Cruciform Building, Gower Street, London WC1E 6BT, United Kingdom.
authors: Neil P
authors: NP
authors: Jones
authors: †Oncology Innovative Medicines Unit, AstraZeneca, 35S47 Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors: Jason G
authors: JG
authors: Kettle
authors: †Oncology Innovative Medicines Unit, AstraZeneca, 35S47 Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors: Scott
authors: S
authors: Lamont
authors: †Oncology Innovative Medicines Unit, AstraZeneca, 35S47 Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors: Hilary J
authors: HJ
authors: Lewis
authors: †Oncology Innovative Medicines Unit, AstraZeneca, 35S47 Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors: Philip
authors: P
authors: MacFaull
authors: ‡CRT Discovery Laboratories, Jonas Webb Building (B910), Babraham Research Campus, Cambridge, CB22 3AT, United Kingdom.
authors: Sheila B
authors: SB
authors: McLoughlin
authors: ‡CRT Discovery Laboratories, Jonas Webb Building (B910), Babraham Research Campus, Cambridge, CB22 3AT, United Kingdom.
authors: Laurent J M
authors: LJ
authors: Rigoreau
authors: ‡CRT Discovery Laboratories, Jonas Webb Building (B910), Babraham Research Campus, Cambridge, CB22 3AT, United Kingdom.
authors: James M
authors: JM
authors: Smith
authors: †Oncology Innovative Medicines Unit, AstraZeneca, 35S47 Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors: Steve
authors: S
authors: St-Gallay
authors: §CRT Discovery Laboratories, Wolfson Institute for Biomedical Research, University College London, The Cruciform Building, Gower Street, London WC1E 6BT, United Kingdom.
authors: Julie K
authors: JK
authors: Stock
authors: §CRT Discovery Laboratories, Wolfson Institute for Biomedical Research, University College London, The Cruciform Building, Gower Street, London WC1E 6BT, United Kingdom.
authors: Andrew P
authors: AP
authors: Turnbull
authors: §CRT Discovery Laboratories, Wolfson Institute for Biomedical Research, University College London, The Cruciform Building, Gower Street, London WC1E 6BT, United Kingdom.
authors: Edward R
authors: ER
authors: Wheatley
authors: †Oncology Innovative Medicines Unit, AstraZeneca, 35S47 Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors: Jon
authors: J
authors: Winter
authors: †Oncology Innovative Medicines Unit, AstraZeneca, 35S47 Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors: Jonathan
authors: J
authors: Wingfield
mesh_terms: D000284:Administration, Oral; D000818:Animals; D002460:Cell Line; D015195:Drug Design; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D025481:Phosphofructokinase-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; C107345:PFKFB3 protein, human; D025481:Phosphofructokinase-2