TG-4260

TG-4260 is a small molecule pharmacological chaperone (pharmacoperone) designed to treat glioblastoma (GBM) by targeting the human telomerase reverse transcriptase (hTERT) promoter. In approximately 86% of GBM tumors, somatic mutations in the hTERT promoter (specifically at -124 or -146 bp) impair the folding of a G-quadruplex silencer element, leading to hTERT overexpression and tumor maintenance. TG-4260 binds to the 26-mer base-pair heteroduplex loop, which serves as the nucleation site for the cooperative folding of the major 5-12 G-quadruplex. By correcting this misfolding, TG-4260 restores the silencer function of the G-quadruplex, resulting in reduced hTERT transcription and activity. This inhibition leads to the suppression of the anti-apoptotic gene BCL2, activation of caspase-3, and induction of cell-cycle arrest and senescence-like phenotypes in glioma cells, while sparing normal human astrocytes.