The Design, Synthesis, and Investigation into Small Molecule Modulators of the Src Homology 2 Domain-Containing Inositol 5’-Phosphatase (SHIP)
Date of Award
Doctor of Philosophy (PhD)
Chemistry | Organic Chemistry
The PI3K pathway is a major cell signaling pathway that influences survival and longevity in eukaryotic cells. Abnormal signaling of this pathway has been implicated in a number of disorders, including Alzheimer's disease and cancer. The PI3K pathway utilizes the inositolphospholipid PI(3,4,5)P3 as a key secondary messenger in the transmission of signals from outside the cell to the nucleus. The SRC Homology 2 containing Inositol 5’-Phosphatase (SHIP) also plays a key role in the PI3K pathway, mediating hydrolysis of the inositol phospholipid PI(3,4,5)P3 to PI(3,4)P2. Early testing has shown modulation of SHIP activity through the use of small molecule modulators is effective at treating certain types of cancer and inflammatory diseases in cell-based assays and in murine xenografts.This report details the investigation into tryptamine-based pan-SHIP1/2 inhibitors, as well as studies into a newly discovered sulfonamide-based SHIP1 selective agonist. Attempts to modulate SHIP activity by means of small molecules led us to develop and synthesize various small molecule tryptamine inhibitors in hopes of increasing the selectivity and potency, as well as probe the structure-activity relationships. The recently uncovered bis-sulfonamide SHIP1 agonist was synthesized for preliminary testing and investigation. Additionally, studies were undertaken to design and synthesis new sulfonamide-based SHIP1 agonists allowing for the development of more potent agonists that are less likely to biodegrade when exposed to CYP enzymes.
Meyer, Shea Thomas, "The Design, Synthesis, and Investigation into Small Molecule Modulators of the Src Homology 2 Domain-Containing Inositol 5’-Phosphatase (SHIP)" (2022). Dissertations - ALL. 1588.