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The 20S Proteasome as a Target for Novel Cancer Therapeutics: Development of Proteasome Inhibitors and Proteolysis-Targeting Chimeras (PROTACs)

Tokarski, Robert James, II
http://orcid.org/0000-0003-0621-0909
http://rave.ohiolink.edu/etdc/view?acc_num=osu1587559789211309

Abstract Details

2020, Doctor of Philosophy, Ohio State University, Pharmacy.
Hematological cancers are a collection of blood-borne malignancies that manifest in the bone marrow, where development of mutations in red blood cells, white blood cells, and platelets disrupts the production of healthy blood cells. Depending upon the type of blood cell affected, hematological malignancies can arise in the form of lymphoma, multiple myeloma, and leukemia, with the cancerous blood cells traveling throughout the body via the vascular system. The movement of cancerous blood cells complicates treatment, as the mutated cells can travel to and affect healthy cells throughout the blood and in the bone marrow. Treatment regiments for hematological malignancies have been and currently are being developed. Since patients can either show no response to first-line therapies or relapse even after successful first-line treatment, novel therapeutics to overcome the issue of resistance to first-line therapeutics are needed. Mainly, these novel therapeutics target key proteins that play crucial roles in the rapid growth and proliferation of cancerous blood cells. One key protein is the human 26S (also known as the 20S) proteasome, the control center for protein degradation in the ubiquitin proteasome pathway (UPP), the major pathway for protein catabolism in cells. Due to its role in controlling protein expression, proteasomal activity is upregulated in hematological cancer cells, as these cells require high levels of protein turnover to maintain growth and proliferation. This crucial role of ensuring rapid protein turnover in cancer cells makes the proteasome an advantageous target for cancer therapeutics. Chapter 1 of this thesis goes into further detail about hematological malignancies, the human 26S proteasome, and the proteasome’s oncological role. This thesis also presents two therapeutic routes, both with the potential to treat hematological malignancies, that utilize the human 26S proteasome. In Chapter 2, work to synthesize the natural product scytonemide A and structurally related analogues, in efforts to develop a novel proteasome inhibitor, is presented. As seen with other proteasome inhibitors that have been FDA approved, shutting down the activity of the 26S proteasome is therapeutically effective – proteasomal inhibition shuts down protein degradation in the cancer cell, causing the buildup of ubiquitinated proteins that eventually induces apoptosis. In Chapter 3, the design, synthesis, and development of a targeted CDK9 degrader molecule is presented. The emerging field of proteolysis-targeting chimeras (PROTACs), molecules that utilize the 26S proteasome to specifically degrade a protein of interest via targeted protein degradation, can effectively knock out a protein from a cancer cell altogether. The PROTAC technology can be used to target a protein like CDK9 – vital for controlling a pathway needed for proliferation and growth in a cancer cell. Once CDK9, a regulator of transcription in cancer cells, is knocked out, the cancer cell is unable to recover and cannot effectively reproduce adequate amounts of the key protein necessary for continued growth, leading to apoptosis of the cancer cell. Overall, novel proteasome inhibitors and PROTACs hold tremendous promise in the continued development of novel anticancer therapeutics, especially in overcoming resistance seen for first-line therapies administered in hematological malignancies.
James Fuchs, PhD (Advisor)
Karl Werbovetz, PhD (Committee Member)
Liva Rakotondraibe, PhD (Committee Member)
522 p.
Pharmacy Sciences
26S Proteasome; PROTACs; Proteasome Inhibition; Targeted Protein Degradation; Anticancer Therapeutics; Hematology Oncology; Total Synthesis; Natural Product

Recommended Citations

Citations

  • Tokarski, II, R. J. (2020). The 20S Proteasome as a Target for Novel Cancer Therapeutics: Development of Proteasome Inhibitors and Proteolysis-Targeting Chimeras (PROTACs) [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1587559789211309

    APA Style (7th edition)

  • Tokarski, II, Robert. The 20S Proteasome as a Target for Novel Cancer Therapeutics: Development of Proteasome Inhibitors and Proteolysis-Targeting Chimeras (PROTACs). 2020. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1587559789211309.

    MLA Style (8th edition)

  • Tokarski, II, Robert. "The 20S Proteasome as a Target for Novel Cancer Therapeutics: Development of Proteasome Inhibitors and Proteolysis-Targeting Chimeras (PROTACs)." Doctoral dissertation, Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1587559789211309

    Chicago Manual of Style (17th edition)

osu1587559789211309
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This open access ETD is published by The Ohio State University and OhioLINK.