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Medicinal Chemistry Drug Discovery Efforts Towards Anticancer Leads: The Development of CDK9-Targeting PROTAC and PHY-34 Analogues

Mize, Brittney K
http://rave.ohiolink.edu/etdc/view?acc_num=osu1681913524279521

Abstract Details

2023, Doctor of Philosophy, Ohio State University, Pharmaceutical Sciences.
Cancer is a pervasive, multifaceted, disease that is among the leading causes of death world-wide. Disease onset and development is often complex in nature and can take on many forms in the body. Therefore, the success of current localized and systemic treatment options can be limited. It is estimated that by 2040, the number of cancer related deaths will rise to approximately 6.9 million more people per year. The need for more effective and diverse anticancer therapeutics is crucial for patient survival. In the first project, anticancer drug discovery efforts have focused on the development of proteolysis targeting chimeras (PROTACs). The design and synthesis of this class of protein degraders has emerged as a technique for the selective targeting of kinases such as cyclin-dependent kinases (CDKs). Cyclin-dependent kinase 9 (CDK9) is a key cancer promoter in acute myeloid leukemia. Due to its high degree of homology to other CDK isoforms, it is a difficult protein to target. Two different investigations of protein targeting ligands (AT7519 and BAY-958) with varying linker length have been investigated with less than 100 nM in vitro potency being achieved. While in vivo efficacy has yet to be achieved, the optimization of PROTACs and their drug properties is ongoing. In the second project, we utilize a more traditional approach to drug development through the modification and optimization of a series of natural products. Arylnaphthalene lignan lactones, a class of natural products isolated from plants in the Phyllanthaceae family, have been found to display a diverse range of antitumor, anti-inflammatory, and antiviral properties. Through structural manipulation, efforts have been made to increase the potency and probe the mechanism of action of various members of this class. Previously, the Kinghorn lab reported the isolation of two related series of arylnaphthalene lignan lactones, the phyllanthusmins and the acutissimalignans from Phyllanthus poilanei and Phyllanthus songboiensis, respectively. These natural products, which showed promising cytotoxicity in a number of cancer cell lines, served as lead compounds for a thorough structure-activity relationship analysis that led to the development of the highly potent compound PHY-34. PHY-34 has shown low- to sub-nanomolar potency in several solid-tumor cell lines and promising in vivo data in an OVCAR8 xenograft model. Subsequent optimization of PHY-34 has focused on selective functionalization of the glycone portion of PHY-34 to probe cell line selectivity, increase stability, and develop mechanistic probes. Comparison of NCI 60 profiles and analysis of in vitro efficacy in a series of cell lines developed by Novartis has been carried out, suggesting that these compounds interact with the membrane-associated ATP6V0A2 subunit of the vacuolar ATPase (v-ATPase). Recent molecular docking studies have aided in the visualization of our natural product hit (PHY-D) and synthetic lead (PHY-34) interacting with v-ATPase. Diversification of anticancer drug discovery will give clinicians the options they need to fight such a complex disease in the future.
James Fuchs (Advisor)
Chemistry

Recommended Citations

Citations

  • Mize, B. K. (2023). Medicinal Chemistry Drug Discovery Efforts Towards Anticancer Leads: The Development of CDK9-Targeting PROTAC and PHY-34 Analogues [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1681913524279521

    APA Style (7th edition)

  • Mize, Brittney. Medicinal Chemistry Drug Discovery Efforts Towards Anticancer Leads: The Development of CDK9-Targeting PROTAC and PHY-34 Analogues . 2023. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1681913524279521.

    MLA Style (8th edition)

  • Mize, Brittney. "Medicinal Chemistry Drug Discovery Efforts Towards Anticancer Leads: The Development of CDK9-Targeting PROTAC and PHY-34 Analogues ." Doctoral dissertation, Ohio State University, 2023. http://rave.ohiolink.edu/etdc/view?acc_num=osu1681913524279521

    Chicago Manual of Style (17th edition)

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