Date on Master's Thesis/Doctoral Dissertation

12-2017

Document Type

Master's Thesis

Degree Name

M.S.

Department

Pharmacology and Toxicology

Degree Program

Pharmacology and Toxicology, MS

Committee Chair

States, J. Christopher

Committee Co-Chair (if applicable)

Wise, John P.

Committee Member

Wise, John P.

Committee Member

Trent, John O.

Committee Member

Damodaran, Chendil

Committee Member

Li, Chi

Author's Keywords

APC/C; mitosis; cancer; mitotic inhibitors; chemotherapy; drug development

Abstract

Mitosis-inhibiting chemotherapeutics (e.g. taxanes) are frequently used to treat multiple cancer types. Recently, there has been much concern about the limited success of these drugs due to resistance and a lack of molecular targets. Thus, there is high demand for new drugs with diverse cellular targets. Targeting the regulators of mitosis is a promising approach. The anaphase promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that controls cell cycle progression at multiple points. The interaction of ANAPC2 and ANAPC11, catalytic core subunits, is necessary for APC/C function. An in silico approach was used to identify compounds predicted to prevent assembly of ANAPC2 and ANAPC11, causing APC/C inhibition and mitotic arrest. Several of the predicted compounds possess cytotoxic properties in multiple cancer cell types. These hit compounds induce mitotic arrest and cell death in malignant, but not non-malignant cells. Additionally, hit compounds are effective in taxane-resistant cells.

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