Date of Completion
Matthew Kyle Hadden
Doctor of Pharmacy
Pharmacy and Pharmaceutical Sciences
My projects were to evaluate itraconazole (ITZ) analogues as anti-cancer hedgehog (Hh) and angiogenesis inhibitors, and translesion synthesis (TLS) inhibitors as anti-cancer agents. Itraconazole (ITZ) is a clinically effective triazole antifungal agent that has also been identified for its anti-cancer properties. As reported in the current literature, ITZ inhibits Gli1 transcription of the Hedgehog (Hh) signaling pathway and angiogenesis. However, the triazole moiety of ITZ has a detrimental side effect of inhibiting cytochrome P450 3A4 enzymes (CYP3A4). Thus, we have removed the triazole from the ITZ scaffold and develop a new series of ITZ analogues called des-triazole ITZ analogues. The purpose of this study was to determine whether des-triazole ITZ analogues would retain both anti-Hh and anti-angiogenic activity and explore how ITZ inhibits both these physiological processes. The translesion synthesis (TLS) pathway is a major mechanism through which cancer cells replicate past DNA lesions and promote chemoresistance. TLS allows cancers to survive genotoxic chemotherapy and increases the rate of mutation in tumors leading to drug-resistant cells. Cancer cells use a set of specialized low-fidelity TLS DNA polymerases to copy over lesions with Rev1 serving as a key scaffolding protein. Suppressing Rev1 activity sensitizes cancers to genotoxic chemotherapy and reduces the onset of chemoresistance by decreasing tumor mutation rate. Disruption of the Rev1/polζ-dependent TLS selective inhibitors has demonstrated the ability to sensitize cancer cells to platinating agents and reduce mutagenesis in tumors. This study identifies small molecule Rev1/polζ-dependent TLS inhibitors and validates the anti-cancer effects of combination cisplatin and TLS inhibitors.
Chan, Kelly Allison, "Evaluating Itraconazole Analogues and Translesion Synthesis Inhibitors as Anti-Cancer Agents" (2018). Honors Scholar Theses. 576.