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Drug Development Efforts Towards Discovery, Characterization and Development of Efficacious Anti-Virulence Agents Against Bacteria and Protein Degraders for Acute Myeloid Leukemia

Ayinde, Oluwatosin Rebecca
http://rave.ohiolink.edu/etdc/view?acc_num=osu1680802710666049

Abstract Details

2023, Doctor of Philosophy, Ohio State University, Pharmacy.
In this work, medicinal chemistry principles and methods were applied for the development of novel therapies against Avian Pathogenic Escherichia Coli (APEC) and Acute Myeloid Leukemia (AML). Avian Pathogenic Escherichia Coli (APEC) is a gram-negative bacterium that infects poultry animals and is responsible for millions in annual financial losses in the broiler industry. The threat of bacterial resistance presents a major challenge to the development of anti-bacterial therapies for APEC, as with many other bacterial infections. For this reason, there have been multiple reports describing efforts to develop anti-virulence agents as opposed to cytotoxic antibiotics. Targeting anti-virulence mechanisms within bacteria has been shown to reduce pathogenicity while demonstrating lower susceptibility to resistance development. In Chapter 1, the current practices and therapies used in the broiler industry to manage APEC are discussed, as well as the major anti-virulence research discoveries that have been made. Chapter 2 focuses on the synthetic strategies employed herein, for the optimization of novel anti-virulence agents against APEC. Acute Myeloid Leukemia is a disease of the blood that is characterized by the prevalence of immature stem cells that are produced in the bone marrow. Cyclin Dependent Kinase 9 (CDK9) has been identified as a therapeutically relevant target in AML. In Chapter 3, it is shown how several inhibitors have demonstrated efficacy in vitro and in early clinical trials and how, unfortunately, none have successfully gained approval for use in treating diseased patients. Failure of these drugs is largely due to the low efficacy and severe side effects that are often observed as a result of administering these small molecule inhibitors. In Chapter 3, an alternative mode of engagement of CDK9 is discussed, wherein Proteolysis Targeting Chimeras (PROTACs) are introduced. In this chapter, the potential advantages of PROTACs over traditional inhibitors are discussed as well as the strategies that are currently being employed for the optimization of degrader properties. Finally, in Chapter 4, the design, synthesis and characterization of several CDK9 degraders is discussed and provides insight into how medicinal chemistry can be employed as a tool to optimize the potency and physicochemical properties of a class of compounds with relatively extreme structural characteristics.
James Fuchs (Advisor)
Liva Rakotondraibe (Committee Member)
Xiaolin Cheng (Committee Member)
Blake Peterson (Committee Member)
Pharmacy Sciences

Recommended Citations

Citations

  • Ayinde, O. R. (2023). Drug Development Efforts Towards Discovery, Characterization and Development of Efficacious Anti-Virulence Agents Against Bacteria and Protein Degraders for Acute Myeloid Leukemia [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1680802710666049

    APA Style (7th edition)

  • Ayinde, Oluwatosin. Drug Development Efforts Towards Discovery, Characterization and Development of Efficacious Anti-Virulence Agents Against Bacteria and Protein Degraders for Acute Myeloid Leukemia. 2023. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1680802710666049.

    MLA Style (8th edition)

  • Ayinde, Oluwatosin. "Drug Development Efforts Towards Discovery, Characterization and Development of Efficacious Anti-Virulence Agents Against Bacteria and Protein Degraders for Acute Myeloid Leukemia." Doctoral dissertation, Ohio State University, 2023. http://rave.ohiolink.edu/etdc/view?acc_num=osu1680802710666049

    Chicago Manual of Style (17th edition)

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This open access ETD is published by The Ohio State University and OhioLINK.