Date of Award
2025
Document Type
Thesis
Degree Name
MS in Science
Department
Pharmaceutical Sciences
First Advisor
Aaron Muth
Second Advisor
Vikas Dukhande
Third Advisor
Vijaya Korlipara
Abstract
Glioblastoma multiforme (GBM) is a highly proliferative brain tumor that has a 5-year survival rate of ~7 %. Temozolomide (TMZ) is the current standard of care therapeutic for GBM. However, 50% of patients develop resistance to TMZ. Therefore, further investigation for new GBM therapeutics is necessary to overcome this issue of drug resistance. GBM patients are known to overexpress lactate dehydrogenase (LDH), which is inversely correlated with their survival. This key glycolytic enzyme catalyzes the interconversion of pyruvate and lactate and plays an important role in cancer proliferation and invasion. Therefore, we aimed to inhibit LDH for developing therapeutics for GBM. In our previous study, we demonstrated the efficacy of a putative LDH inhibitor Stiripentol (STP) against GBM as. STP is an FDA-approved drug used for the treatment of Dravet Syndrome (a rare epilepsy). We repurposed STP for its potential as a novel GBM therapeutic. However, our previous data showed that STP moderately inhibits LDH and shows suboptimum potency in GBM cells. Therefore, we aimed to do an extensive structure-activity relationship (SAR) study of the STP scaffold to develop novel and potent analogs. We focused on replacing the tertiary butyl group of STP with various aromatic substitutions or various bulky groups to enhance GBM cytotoxicity and improve LDH inhibition. The synthesized STP analogs were evaluated for their cytotoxic and anti-proliferative activity (CC50) against four human GBM cell lines (U87, U138, SW1088, and LN229) by MTT and CyQuant assays. The results indicate an enhanced cytotoxic profile of select STP analogs in comparison to the parent compound. The selectivity of the active compounds was also evaluated against non-cancerous HEK-293 cells. Further biological evaluation will include assessing LDH enzyme activity inhibition. Future studies will focus on lead optimization of our most potent analogs.
Recommended Citation
Jain, Anshika Y., "DEVELOPING STIRIPENTOL ANALOGS AS POTENTIAL LDH INHIBITORS FOR THE TREATMENT OF GLIOBLASTOMA" (2025). Theses and Dissertations. 856.
https://scholar.stjohns.edu/theses_dissertations/856