The inositol phosphatase SHIP1 is a key participant in the PI3K pathway, a major cellular signaling axis. Alteration of SHIP1 activity may provide a means to increase blood cell production and facilitate bone marrow transplantation. While gene knockouts can be used to explore the biochemical role of SHIP1, the enzyme also acts as a docking protein, which recruits other enzymes to the cell membrane. Deconvoluting the phosphatase activity from structural functions is therefore difficult utilizing only genetic tools. To gain more insight into the role of SHIP1, small molecule inhibitors of the enzymes phosphatase activity were found using high throughput screening. This method identified several aminosteroids as inhibitors of SHIP1. Both synthetic studies that have been undertaken to explore pharmacophoric relationships and improve water solubility as well as the preliminary biological evaluation of these molecules will be presented.

Aminosteroid inhibitors of the inositol phosphatase SHIP1

248th National Meeting (2014)

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