Regioisomeric family of novel fluorescent substrates for SHIP2

Gaye White, Christopher Prior, Stephen J. Mills, Kendall Baker, Hayley Whitfield, Andrew M. Riley, Vasily S. Oganesyan, Barry V. L. Potter, Charles A. Brearley

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SHIP2 (SH2-domain containing inositol 5-phosphatase type 2) is a canonical 5-phosphatase which, through its catalytic action on PtdInsP3, regulates the PI3K/Akt pathway and metabolic action of insulin. It is a drug target but there is limited evidence of inhibition of SHIP2 by small molecules in the literature. With the goal to investigate inhibition, we report a homologous family of synthetic, chromophoric benzene phosphate substrates of SHIP2 that display the headgroup regiochemical hallmarks of the physiological inositide substrates that have proved difficult to crystallize with 5-phosphatases. Using time-dependent density functional theory (TD-DFT), we explore the intrinsic fluorescence of these novel substrates and show how fluorescence can be used to assay enzyme activity. The TD-DFT approach promises to inform rational design of enhanced active site probes for the broadest family of inositide-binding / metabolizing proteins, whilst maintaining the regiochemical properties of bona fide inositide substrates.
Original languageEnglish
Pages (from-to)309-315
Number of pages7
JournalACS Medicinal Chemistry Letters
Issue number3
Early online date18 Oct 2019
Publication statusPublished - 12 Mar 2020


  • 5-phosphatase
  • HPLC
  • Inositol phosphate
  • SHIP2
  • TD-DFT
  • fluorescence
  • ligand

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