Thesis advisor: Charles Hoffman / The second messenger cyclic 3’-5’ adenosine monophosphate (cAMP) signaling pathway plays an important physiological role in many organisms. Cyclic nucleotide phosphodiesterases (PDEs) regulate signal transduction by catalyzing the hydrolysis of cAMP and cGMP allowing for the downregulation of cyclic nucleotide levels. Human PDEs are encoded by 21 genes grouped into 11 families. The biological role of the most recently discovered PDE family (PDE11) remains poorly understood partly due to the lack of selective inhibitors. Mutations in the PDE11A gene have been linked to a wide range of diseases, such as Cushing Syndrome, which is a result of inactivating mutations expressed in adrenocortical tumors. Meanwhile, PDE11 levels are seen to increase in the ventral hippocampus as a function of aging, and is associated with a loss of social memory. Thus, the development of a selective PDE11 inhibitor could provide a potential therapeutic benefit to patients receiving long-term corticosteroid treatment by stimulating cortisol production by the adrenal gland, as well as to aging adults to maintain social memory. To address these needs, candidate PDE11 inhibitors related to a compound discovered by the Hoffman lab in a high throughput screen for PDE11 inhibitors are being synthesized by the Rotella laboratory. I have been evaluating these compounds using two fission yeast-based growth assays in complement with in vitro enzyme assays carried out by Dr. Jeremy Eberhard.
Here I describe my role in the project, leading to the identification of a compound, SMQ2-57, which is a selective inhibitor of the PDE11 enzyme whose potency has been confirmed through both yeast-based assays and in vitro enzyme assays. In addition, I have taken both a forward and reverse genetic approach to identify PDE11A4 mutant alleles that confer resistance to inhibitor compounds as such knowledge could guide a rational drug design approach to produce more effective PDE11 inhibitors. Based on our results, SMQ2-57 could serve as a useful tool in understanding the biological role of PDE11. Meanwhile, data from my study of compound resistant mutant PDE11 alleles should allow for the characterization of the physical interaction between PDE11 and its inhibitors in an effort to guide a medicinal chemistry program to develop a more potent and drug-like PDE11 inhibitor. / Thesis (BS) — Boston College, 2023. / Submitted to: Boston College. College of Arts and Sciences. / Discipline: Scholar of the College. / Discipline: Biology.
| Identifer | oai:union.ndltd.org:BOSTON/oai:dlib.bc.edu:bc-ir_109790 |
| Date | January 2023 |
| Creators | Ly, Judy |
| Publisher | Boston College |
| Source Sets | Boston College |
| Language | English |
| Detected Language | English |
| Type | Text, thesis |
| Format | electronic, application/pdf |
| Rights | Copyright is held by the author, with all rights reserved, unless otherwise noted. |
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