Regioisomeric family of novel fluorescent substrates for SHIP2

Journal article

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, while maintaining the regiochemical properties of bona fide inositide substrates.

Authors: White, G; Prior, C; Mills, S; Riley, A; Potter, B

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Chemical Society
• Journal: ACS Medicinal Chemistry Letters
• Volume: 11
• Issue: 3
• Pages: 309-315
• Publication date: 2019-10-18
• Acceptance date: 2019-10-18
• DOI: 10.1021/acsmedchemlett.9b00368
• EISSN: 1948-5875
• ISSN: 1948-5875
• Language: English
• Keywords: FFR