A Novel Technology Involving Cell Signaling, the PI3K Pathway: SHIP1 and SHIP2 Inhibitors

Different classes of these SHIP inhibitory compounds are effective in murine models of diseases including cancer, diabetes, and Alzheimer’s.
Background: Reversible phosphorylation of inositol lipids controls diverse functions in cells. Phosphatidylinositol can be phosphorylated on three free hydroxyls, forming a number of different species with distinct roles in signal transduction. PI3K transmits signals that regulate a variety of physiological processes in virtually all tissue types. Medicinal chemistry has been used to create PI3K pathway inhibitors which can be tested for their ability to activate or inhibit disease-related processes. Mice with mutations in PI3K genes have also been used for functional studies. The study of PI3K enzymes and how they function in different cell types has shown that they are implicated in a wide range of diseases and dysfunctions, due to their influence on cell growth, proliferation, metabolism and secretion, particularly as it relates to immune cell development and pathogen defense. Deviations in PI3K signaling have been associated with immunologic, neurologic, cardiovascular, endocrine, and oncologic disorders. Technology Overview: The Src homology (SH2) containing Inositol 5-phosphatases SHIP1 and SHIP2 are key members of the critical PI3K cell signaling pathway described above, and they have a wide-ranging influence over cells. Because of their unique capacity to hydrolyze the PI3K product PI(3,4,5)P3 and convert it to PI(3,4)P2 at the plasma membrane, SHIP1 and SHIP2 have essential roles in cell signaling that can result in either inhibition or facilitation of PI3K signaling. SUNY Upstate Medical researchers have isolated and characterized small molecules that act as SHIP1, pan-SHIP1/2 or SHIP2 inhibitors. Moreover, his lab has shown that different classes of these SHIP inhibitory compounds are effective in murine models of disease including cancer, obesity, diabetes, and Alzheimer’s disease, as well as in tumor immunotherapy, pathogen resistance, bone marrow transplantation, stem cell expansion/mobilization, and blood cell recovery. SHIP1 is expressed primarily in mesynchymal stem cells and hematolymphoid cells, while SHIP2 is more ubiquitous; thus, different SHIP inhibitors are optimal in different disease contexts. The research lab is currently combining high-resolution structures of the SHIP1 and SHIP2 enzymatic domains and medicinal chemistry to develop novel small molecule inhibitors with enhanced potency, specificity and solubility. They are employing gene editing to understand the structural requirements for different classes of SHIP inhibitors; and they are continuing to do in vivo studies in genetic models to elucidate the ways in which different classes of SHIP inhibitors act to prevent or reverse disease. Further Details: 1. Biochem Soc Trans (2020) 48 (1), 291 “300; https://doi.org/10.1042/BST20190775 2. Cancers 2021, 13 (4), 890; https://doi.org/10.3390/cancers13040890 Intellectual Property Summary: Multiple Patents Licensing Potential: Licensing, Development partner Licensing Status: Seeking licensing and research collaboration to move optimal research candidates into clinical trials and beyond. https://suny.technologypublisher.com/files/sites/istock-1046016016.jpg



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