iMQT_020 is a selective allosteric SLC1A5_var inhibitor. It disrupts the trimer assembly of SLC1A5_var, leading to a metabolic crisis in cancer cells and selectively inhibiting their growth. iMQT_020 reduces compensatory glutamine metabolism and oxidative phosphorylation, causing widespread metabolic disruption in cancer cells. It lowers GSH levels while increasing intracellular and mitochondrial ROS levels. Additionally, iMQT_020 induces apoptosis and ferroptosis and upregulates PD-L1 expression through epigenetic mechanisms. This compound is applicable in research on pancreatic, lung, and colon cancers.

iMQT_020, at a concentration of 10 μM, exhibits the strongest inhibition of mitochondrial glutamine uptake (IC 50 = 6.156 μM). This compound (0-100 μM) binds directly to wild-type SLC1A5_var protein (K d = 4.473 μM) but does not bind to the FIL/AAA mutant. At 4 μM, iMQT_020 significantly reduces the circular dichroism (CD) signal of the wild-type SLC1A5_var protein, indicating structural alteration. It also lowers the levels of glutamine-derived TCA cycle metabolites (such as glutamate, α-ketoglutarate, succinate) and their downstream products (like glutathione, proline) in MIA PaCa-2 cells at 10 μM. Additionally, at 10 μM for 24 hours, iMQT_020 decreases the levels of GSH, increases intracellular and mitochondrial ROS in these cells, and reduces the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in MIA PaCa-2 cells overexpressing SLC1A5_var WT, but not in the FIL/AAA mutant. This concentration for the same duration also alters mitochondrial morphology by reducing fragmentation and decreases mitochondrial membrane potential (evidenced by reduced TMRE staining). iMQT_020 selectively inhibits the viability of cancer cells (IC 50 5-40 μM) without affecting normal cells after 48 hours. Furthermore, 10 μM of this compound for 24 hours upregulates PD-L1 mRNA and protein expression in human PDAC cell lines (e.g., SU.86.86, SW1990) and mouse cancer cell lines (KPC, LLC, MC-38).

iMQT_020 administered at a dosage of 75 mg/kg via intraperitoneal injection once daily for 35 days, suppresses tumor growth in MIA PaCa-2 cell xenograft mice by inducing apoptosis and ferroptosis. The same treatment regimen also inhibits tumor proliferation in the MIA PaCa-2 murine orthotopic transplant model. Additionally, iMQT_020 prevents tumor growth in NCI-H1299 human lung cancer and COLO 205 human colorectal cancer xenograft mice under similar conditions. Moreover, when used in combination with anti-PD-L1 antibody (aPD-L1) at 25 mg/kg once daily for 21 days, iMQT_020 synergistically hinders the growth of syngeneic tumors formed by KPC, LLC, or MC-38 cells in mice.