Discovery and Development of Small Molecule SHIP Phosphatase Modulators

Dennis R. Viernes, Lydia B. Choi, William G. Kerr, John D. Chisholm

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

Inositol phospholipids play an important role in the transfer of signaling information across the cell membrane in eukaryotes. These signals are often governed by the phosphorylation patterns on the inositols, which are mediated by a number of inositol kinases and phosphatases. The src homology 2 (SH2) containing inositol 5-phosphatase (SHIP) plays a central role in these processes, influencing signals delivered through the PI3K/Akt/mTOR pathway. SHIP modulation by small molecules has been implicated as a treatment in a number of human disease states, including cancer, inflammatory diseases, diabetes, atherosclerosis, and Alzheimer's disease. In addition, alteration of SHIP phosphatase activity may provide a means to facilitate bone marrow transplantation and increase blood cell production. This review discusses the cellular signaling pathways and protein-protein interactions that provide the molecular basis for targeting the SHIP enzyme in these disease states. In addition, a comprehensive survey of small molecule modulators of SHIP1 and SHIP2 is provided, with a focus on the structure, potency, selectivity, and solubility properties of these compounds.

Original languageEnglish (US)
Pages (from-to)795-824
Number of pages30
JournalMedicinal Research Reviews
Volume34
Issue number4
DOIs
StatePublished - Jul 2014

Keywords

  • Drug development
  • Enzyme agonist
  • Enzyme inhibition
  • Inositol phosphatase
  • PI3K
  • SHIP

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology
  • Drug Discovery

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