Identification of Small-Molecule Inhibitors of Human Inositol Hexakisphosphate Kinases by High-Throughput Screening

Gangling Liao, Wenjuan Ye, Tyler Heitmann, Glen Ernst, Michael Depasquale, Laiyi Xu, Michael Wormald, Xin Hu, Marc Ferrer, Robert K. Harmel, Dorothea Fiedler, James Barrow, Huijun Wei

Research output: Contribution to journalArticlepeer-review


Inositol hexakisphosphate kinases (IP6Ks) catalyze pyrophosphorylation of inositol hexakisphosphate (IP6) into inositol 5-diphospho-1,2,3,4,6-pentakisphosphate (IP7), which is involved in numerous areas of cell physiology including glucose homeostasis, blood coagulation, and neurological development. Inhibition of IP6Ks may be effective for the treatment of Type II diabetes, obesity, metabolic complications, thrombosis, and psychiatric disorders. We performed a high-throughput screen (HTS) of 158 »410 compounds for IP6K1 inhibitors using a previously developed ADP-Glo Max assay. Of these, 1206 compounds were found to inhibit IP6K1 kinase activity by more than 25%, representing a 0.8% hit rate. Structural clustering analysis of HTS-active compounds, which were confirmed in the dose-response testing using the same kinase assay, revealed diverse clusters that were feasible for future structure-activity relationship (SAR) optimization to potent IP6K inhibitors. Medicinal chemistry SAR efforts in three chemical series identified potent IP6K1 inhibitors which were further validated in an orthogonal LC-MS IP7 analysis. The effects of IP6K1 inhibitors on cellular IP7 levels were further confirmed and were found to correlate with cellular IP6K1 binding measured by a high-throughput cellular thermal shift assay (CETSA).

Original languageEnglish (US)
Pages (from-to)780-789
Number of pages10
JournalACS Pharmacology and Translational Science
Issue number2
StatePublished - Apr 9 2021


  • IP7
  • cellular thermal shift assay (CETSA)
  • high-throughput screen
  • inositol hexakisphosphate kinases
  • inositol pyrophosphate

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)


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