Defense Date

3-20-2024

Graduation Date

Spring 5-18-2024

Availability

One-year Embargo

Submission Type

dissertation

Degree Name

PhD

Department

Medicinal Chemistry

School

School of Pharmacy

Committee Chair

Dr. Patrick T. Flaherty

Committee Member

Dr. Aleem Gangjee

Committee Member

Dr. Marc W. Harold

Committee Member

Dr. Jane Cavanaugh

Committee Member

Dr. Kevin Tidgewell

Keywords

MEK5, ERK5, PI3K, AKT, Dual, Quinazoline, Heterocycles, Sigma

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease that impairs memory and cognitive judgment, mostly in older people. It is the leading cause of dementia in late adult life. The hallmarks of AD include neuronal loss, neuroinflammation, a build-up of extracellular amyloid beta (Aβ) plaques, intracellular neurofibrillary tangles, and extracellular neuritic plaques. Current treatment, although useful, is not adequate. Identification of therapeutic agents with the potential to alter the progress of AD is a high priority. Recent studies suggest that the Sigma-2 receptor is an attractive target for the development of disease-modifying AD drugs. Preventing the binding of Sigma-2 receptors to Aβ oligomers alleviates Aβ-mediated synaptotoxicity in a dose-dependent manner. Using pharmacophore analysis and ligand-based drug design strategies, novel piperazine-containing compounds were designed and synthesized as Sigma-2 receptor antagonists.

The MEK5/ERK5 pathway regulates various cellular processes, including proliferation, differentiation, apoptosis, and migration, and is found to be upregulated in various types of cancer. In triple-negative breast cancer (TNBC), upregulation of the MEK5 pathway is linked to resistance development, poorer relapse-free survival, and activation of epithelial-to-mesenchymal transition (EMT). Therefore, MEK5 is a potential therapeutic target for treating breast cancer, especially TNBC. Additionally, in cancer, overexpression of the PI3K/Akt pathway is also linked to enhanced tumor cell survival and proliferation. The PI3K/Akt and MEK pathways are proposed to be interconnected by crosstalk loops. The dual inhibition of PI3K/Akt and MEK5/ERK5 signaling is found to be more effective at reducing the proliferation and survival of TNBCs than the single inhibition of either pathway alone. Therefore, for effective TNBC treatment, the design and development of selective MEK5 and dual MEK5/PI3K inhibitors were pursued. Literature reported quinazoline derivative was used as the lead compound. The homology model of MEK5 was built using the MEK1 structure (3EQC and 7PQV) to assist in drug design. Extensive lead optimization was conducted using medicinal chemistry approaches, which included surveying variations at the C4 and C6 positions of the quinazoline core along with N-alkyl and hinge binder modifications.

Language

English

Additional Citations

Gumireddy, A.; DeBoyace, K.; Rupprecht, A.; Gupta, M.; Patel, S.; Flaherty, P. T.; Wildfong, P. L. D., Crystal structure of tert-butyl 4-[4-(4-fluorophenyl)-2-methylbut-3-yn-2-yl]piperazine-1-carboxylate. Acta Crystallogr., Sect. E: Crystallogr. Commun., 2021, 77 (4), 360-365.

Bhatt, K. B.; Patel, S.; Matossian, M. D.; Ucar, D. A.; Miele, L.; Burow, M. E.; Flaherty, P. T.; Cavanaugh, J. E., Molecular mechanisms of epithelial to mesenchymal transition regulated by ERK5 signaling. Biomolecules, 2021, 11 (2), 183.

Hoang, V. T.; Matossian, M. D.; La, J.; Hoang, K.; Ucar, D. A.; Elliott, S.; Burks, H. E.; Wright, T. D.; Patel, S.; Bhatt, A.; Phamduy, T.; Chrisey, D.; Buechlein, A.; Rusch, D. B.; Nephew, K. P.; Anbalagan, M.; Rowan, B.; Cavanaugh, J. E.; Flaherty, P. T.; Miele, L.; Collins-Burow, B. M.; Burow, M. E., Dual inhibition of MEK1/2 and MEK5 suppresses the EMT/migration axis in triple-negative breast cancer through FRA-1 regulation. J. Cell. Biochem., 2021, 122 (8), 835-850.

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