T6I-29

**T6I-29** is a novel, chemically unconventional selective estrogen receptor modulator (SERM) based on a tetrahydro-6-isoquinoline (T6I) scaffold, designed as a hybrid of lasofoxifene and RAD1901 (elacestrant). It adopts a unique ligand binding pose in the estrogen receptor alpha (ERα) ligand binding domain (LBD), particularly effective against the Y537S mutant ERα found in endocrine-resistant ER+ breast cancers, forcing the mutation into a therapeutic antagonist conformation. T6I-29 demonstrates significant anti-proliferative activity in breast cancer cells, including those with Y537S ESR1 mutations, outperforming 4-hydroxytamoxifen (4OHT) while matching fulvestrant (ICI), lasofoxifene, and RAD1901; it uniquely downregulates DKK1 (dickkopf-1), a tumor-secreted glycoprotein linked to oncogenesis, Wnt/β-catenin, and PI3K/Akt pathways, reduces SUMO1-related pathways, and impacts cell-cell adhesion and morphology genes. Its potency is being optimized via torsion angle modifications, yielding derivatives like T6I-B2. Developed through structure-activity relationship studies and quantum mechanical calculations, it shows favorable pharmaceutical profiles and reduced metastasis in vivo.[1][2][3][5][7][9][10]

Other names

T6I-29-1AT-6I-29-1AT 6I-29-1A