ETC-501

ETC-501 is a compound that can cross the blood-brain barrier and is effective when administered orally. It acts as a selective inhibitor of MNK1/MNK2, with an IC50 of 0.033 μM for MNK1 and 0.111 μM for MNK2. This compound inhibits the proliferation of glioblastoma cells, impairs DNA damage repair, delays cell cycle progression, and suppresses ribosome biogenesis. Additionally, ETC-501 enhances Temozolomide-induced cellular senescence, reduces the senescence-associated secretory phenotype, and increases cell sensitivity to Navitoclax. It is applicable for research related to glioblastoma.

ETC-501, at concentrations ranging from 0 to 20 μM over 24 hours, exhibits a dose-dependent inhibition of eIF4E phosphorylation and decreases Cyclin D1 protein levels in LN-229 and T98G glioblastoma cells. At doses between 0 and 10 μM, it reduces LN-229 and T98G cell viability with GI50 values of 4.035 μM and 6.122 μM, respectively, and diminishes tumor sphere formation and stem cell frequency in patient-derived GPCs. ETC-501 at 0 to 10 μM over 4 hours damages DNA synthesis in LN-229, T98G, and U-87MG glioblastoma cells in a dose-dependent manner. When administered for 8 hours, it impairs the transition from the G1 phase to the S phase in Palbociclib-synchronized LN-229 and U-87MG cells. Treatment with 5 to 10 μM for 14 days can induce senescence in LN-229 and U-87MG cells. Moreover, administering 5 to 10 μM for 10 days reduces levels of key inflammatory cytokines and chemokines, including IL-6, IL-8, and CCL2. Additionally, 10 μM of ETC-501 in combination with TMZ over 6 days brings LN-229 cells into a pre-senescent state, significantly increasing their sensitivity to Navitoclax-induced cell death and apoptosis.

ETC-501 (100 mg/kg; oral gavage; once daily; 21 days) enhances tumor cell senescence and reduces the senescence-associated secretory phenotype in NSG mice with orthotopic or subcutaneous glioblastoma when used in combination with TMZ. Additionally, further combination with Navitoclax efficiently clears senescent cells.