8018 Improving Anti-Breast Cancer Activities by Optimizing Torsion Angle Energies

Abstract Disclosure: D.R. Zak: None. E.C. Fink: None. G.R. Hancock: None. K.S. Young: None. S.W. Fanning: None. Overexpression of estrogen receptor alpha (ER-alpha) is found in 70% of breast cancer tumors. Normally, ER-alpha remains inactive and sequestered in the cytoplasm until estrogen binds to the ligand-binding domain (LBD) to enable nuclear translocation, coregulator recruitment, and subsequent activation of proliferative ER-alpha-dependent transcriptomic profiles. The majority of breast cancers are treated successfully with ER-targeted endocrine therapies, but hotspot ER-alpha LBD mutants are selected for, namely Y537S and D538G causing therapeutic resistance, relapse, and aggressive metastatic disease. The selective estrogen receptor modulator (SERM) lasofoxifene (laso) and selective estrogen receptor degrader (SERD) elacestrant (RAD1901) are chemically distinctive and show great promise in the ER-alpha mutant setting with potent anti-tumor effects and improved side effect profiles compared to the standard-of-care SERD fulvestrant (ICI). To elucidate the structural-transcriptional relationships of these ligands, we created a laso/RAD1901 chemical hybrid T6I-29 that demonstrated both canonical and unexpected therapeutic mechanisms of action. However, it possesses reduced anti-proliferative potency compared to ICI. We hypothesized that minor chemical changes to T6I-29 could improve potency while maintaining its favorable pharmaceutical profiles. To address this hypothesis, we performed quantum mechanical calculations of a series of T6I-derivatives. The addition of a methyl linker within the scaffold core significantly improved the torsion angle energies of the ligand binding pose. Multiple derivatives were synthesized based on these computations. The new compound T6I-B2 exerted profound anti-proliferative effects on breast cancer cells and adopted a unique ligand binding pose within the LBD. This approach shows that T6I-SERM potency can be improved by optimizing ligand torsion angle energies. Presentation: 6/3/2024