Date of Award
Doctor of Philosophy in Clinical and Bioanalytical Chemistry
Biochemistry, Biomedical Research, Chemistry, Pharmaceuticals
Glioblastoma (GBM) is the most common and aggressive brain tumor, with very poor prognosis. Androgen receptor (AR) plays a significant role in the progression of GBM, and anti-androgen agents have the potential to be used for the treatment of GBM. However, AR mutation commonly happens in GBM, which makes the anti-androgen agents less effective. Heat shock 27 kDa protein (HSP27) is a well-documented chaperone protein to stabilize AR. Inhibition of HSP27 results in AR degradation regardless the mutation status of AR, which makes HSP27 a good target to abolish AR in GBM. Identified compound I ((N-(3-((2,5-dimethoxybenzyl)oxy)-4-(methylsulfonamido) phenyl)-4-methoxybenzamide) inhibits GBM cell growth with IC50s around 5 nM, and also shows significant inhibition in an in vivo GBM xenograft model at 20 mg/kg. Furthermore, it does not show toxicity to mice up to 80 mg/kg, 4-fold higher than the active in vivo dose. The compound significantly induces AR degradation in GBM cells via the proteasomal pathway. These results suggest that targeting HSP27 chaperone function to induce AR degradation in GBM is a promising and novel treatment. Additionally, a sensitive and rapid high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed and validated to investigate the pharmacokinetics and brain distribution of compound I in mice. The method was successfully applied to evaluate the pharmacokinetic of compound I in mouse plasma and brain tissue. The apparent elimination half-life (t1/2) was 4.06 h. The Cmax of compound I in brain tissue was 0.88 μg/g. The results indicated that compound I was rapidly distributed and compound I could cross the blood-brain barrier (BBB). The pharmacokinetic profile summarized provides valuable information for the further investigation of compound I as a potential anti-glioblastoma agent. Ligand based structural optimization in the project identified two novel compounds (compounds 4 and 26) which have potent anti-GBM activity and significantly increased BBB permeability in comparison to the lead compound I. This study indicated that compounds 4 and 26 could be the promising drugs to treat AR over expressed GBM, also provided a meaningful insight for the further structural modification to retain or improve the potency and BBB permeability.
Li, Yaxin, "Targeting Heat Shock 27 Kda Protein Induces Androgen Receptor Degradation" (2022). ETD Archive. 1341.