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J Med Chem. 2015 Apr 23;58(8):3611-25. doi: 10.1021/acs.jmedchem.5b00352. Epub 2015 Apr 13.

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

Author information

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.

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.

PMID:
25849762
DOI:
10.1021/acs.jmedchem.5b00352
[Indexed for MEDLINE]

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