UC Irvine

Abstract Glioblastoma (GBM) has an exceptional high rate of reoccurrence that largely explains its < 15 months median survival. LonP1 is a serine protease that degrades misfolded proteins and regulates mitochondrial DNA replication. It drives tumor progression towards a malignant cancer phenotype in colorectal cancer, melanoma, oral cancer and cervical cancer. Dr. Daniela Bota has previously shown that LonP1 is overexpressed in human malignant gliomas and is associated with higher tumor grade and poor survival prognosis. In collaboration with Professor Bhaskar Das, we have used structure activity Relationship (SAR) analysis to generate compounds with on-target inhibition of LonP1 protease activity. Preliminary work on these novel compounds shows that these proprietary inhibitors can drastically decrease cell viability in the established D54 and U251 GBM lines. The lead compound BT317, shows on-target LonP1 and exceptional chymotrypsin-like proteasome inhibition. This has led to further testing, which has shown that BT317 has enhanced activity against glioma stem cell lines (GSC) and can cause global downregulation of hypoxia inducible factor 1 alpha (Hif1α) in a heterogenous GSC-derived organoid model. Finally, we have demonstrated that BT317 has less activity against differentiated GSC lines (e.g. through successive passages) and appears to have enhanced activity against TNFa-induced, differentiated GSC. This preliminary data highlights combinatorial, pharmacological LonP1 and proteasome inhibition as a novel strategy for targeting GSC in GBM.