title: Discovery and development of small molecule SHIP phosphatase modulators.
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.
authors.affiliation: Department of Chemistry, Syracuse University, Syracuse, NY, USA 13244.
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Viernes
authors.affiliation: Department of Chemistry, Syracuse University, Syracuse, NY, USA 13244.
authors.forename: Lydia B
authors.initials: LB
authors.lastname: Choi
authors.affiliation: Department of Chemistry, Syracuse University, Syracuse, NY, USA 13244.|Department of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY, USA 13210.|Department of Pediatrics, SUNY Upstate Medical University, Syracuse, NY, USA 13210.
authors.forename: William G
authors.initials: WG
authors.lastname: Kerr
authors.affiliation: Department of Chemistry, Syracuse University, Syracuse, NY, USA 13244.
authors.forename: John D
authors.initials: JD
authors.lastname: Chisholm
mesh_terms: D000818:Animals; D004194:Disease; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D000072181:Inositol Polyphosphate 5-Phosphatases; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606430:INPP5D protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
keywords: PI3K; SHIP; drug development; enzyme agonist; enzyme inhibition; inositol phosphatase