Organic Chemistry Seminar – Anunay Pulukuri, Chemistry Graduate Student
About the event
Speaker: Anunay Pulukuri, chemistry graduate student
Title: Acquired drug resistance enhances Imidazoquinoline efflux by P-glycoprotein for Cancer Immunotherapy
Abstract: Multidrug Resistant (MDR) cancers attenuate chemotherapeutic efficacy through drug efflux via ABC (ATP-Binding Cassette) transporters, including P-glycoprotein 1 (P-gp or ABCB1/MDR1). Conversely, Toll-Like Receptor (TLR) agonist immunotherapies modulate activity of tumor-infiltrating immune cells in local proximity to cancer cells and could benefit from the enhanced drug efflux in MDR cancers. However, the effect of acquired drug resistance on TLR agonist efflux is largely unknown. We address this by investigating P-gp mediated efflux of TLR 7/8 agonists. First, we used functionalized liposomes to determine that imidazoquinoline TLR agonists Imiquimod (IMQ), Resiquimod (RSQ), and Gardiquimod (GDQ) are substrates for P-gp and determined their KD values. Interestingly, the least potent imidazoquinoline (IMQ) was the best P-gp substrate. Next, we compared imidazoquinoline efflux in MDR derived cancer cell lines with enhanced P-gp expression relative to parent cancer cell lines. Using P-gp competitive substrates and inhibitors, we observed that imidazoquinoline efflux occurs through P-gp and, for Imiquimod, is enhanced as a consequence of acquired drug resistance. Overall, we concluded that P-gp efflux susceptibility, which correlates to hydrophobicity & cLogP, needs be considered, alongside potency, when choosing the optimal TLR agonist for delivery to MDR cancers. Previous work revolved on Enzyme-Directed Immunostimulant (EDI) prodrugs, with IMQ and RSQ as payloads, however we decided to focus on MDR prostate cancers based on their efflux potential and results from our previous studies. Currently, we are designing small-molecule drug conjugates (SMDCs) that specifically target prostate-specific membrane antigen (PSMA) and comprise of synthesized imidazoquinolines, that are not only highly potent (EC50: ≤ 50 nM), but also fit the parameters required in order to be classified as P-gp substrates. We expect that these SMDCs are exclusively taken up by PSMA (+) prostate cancer cells and following conversion, efflux the imidazoquinoline, with enhanced efflux observed in MDR derived cancer cell lines.