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ToolsWhite, Gaye, Prior, Christopher, Mills, Stephen J., Baker, Kendall, Whitfield, Hayley, Riley, Andrew M., Oganesyan, Vasily S., Potter, Barry V. L. and Brearley, Charles A. (2020) Regioisomeric family of novel fluorescent substrates for SHIP2. ACS Medicinal Chemistry Letters, 11 (3). pp. 309-315. ISSN 1948-5875
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Abstract
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.
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