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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