SHIP1 and the PI3K Pathway – Highlighting the Role of SHIP1 to Reduce Inflammation
Click graphic for enlarged view. (Graphic adapted from Ooms et al.1)
The PI3K pathway is a cellular signaling pathway that has been linked to a diverse group of cellular functions and biological processes such as cell activation and migration, which are related to inflammation, and cell growth, proliferation and survival, which are related to cancer. As a result, the PI3K pathway is heavily researched by the academic community as well as pharmaceutical and biotechnology companies in the areas of immune disorders and cancer.1
Over-activity of the PI3K pathway can cause immune cells to produce an abundance of pro-inflammatory signaling molecules and increase their migration to and concentration in tissues, resulting in excessive or chronic inflammation. By dampening PI3K signaling, small molecules activating SHIP1 may counter inflammation by reducing immune cell migration and activation.
Our approach also targets a unique activation site in SHIP1 called the C2 binding domain.2 We have demonstrated that our lead compounds, bind to the C2 binding domain of SHIP1 thereby increasing its activity, but do not significantly activate or inhibit other enzymes. This specificity and selectivity for activitating SHIP1 may limit potential off-target toxicities. SHIP1 activators target immune cells to reduce inflammation, while minimizing effects in other tissues.
Our scientific co-founders, based at the University of British Columbia, were the first to discover SHIP1 and show that it could be activated by small molecules, thereby demonstrating it as a potential target for a new class of anti-inflammatory drugs. Additionally, academic scientists have shown that certain immune cell cancers have suppressed levels of SHIP1, also making such cancers potential targets for SHIP1 activators.3,4
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1 Ooms, LM, KA Horan, et al. (2009). The role of the inositol polyphosphate 5-phosphatases in cellular function and human disease. Biochem J 419(1): 29-49.
2 Ong, CJ, Ming-Lum, A, et al. (2007). Small-molecule agonists of SHIP1 inhibit the phosphoinositide 3-kinase pathway in hematopoietic cells. Blood 110(6), 1942-1949.
3 Lee, DW, et al. (2012). Loss of SHIP-1 protein expression in high-risk myelodysplastic syndromes is associated with miR-210 and miR-155. Oncogene 31: 4085-4094.
4 Cui, B, et al. (2014). MicroRNA-155 influences B-cell receptor signaling and associates with aggressive disease in chronic lymphocytic leukemia. Blood; 124(4): 546-554.