生物活性

• 描述TACC3 (transforming acidic coiled-coil 3), a transforming acidic coiled-coil (TACC) family member, is frequently upregulated in a broad spectrum of cancers, including breast cancer. It plays critical roles in protecting microtubule stability and centrosome integrity that is often dysregulated in cancers. BO-264 is a potential TACC3 inhibitor having an IC₅₀ of 188 nM. Treatment of JIMT-1 cells with 1 μM BO-264 for 6 hours has led to a considerable stabilization of the cellular TACC3 upon increased temperatures. BO-264 inhibited the viability of basal (MDA-MB-231, MDA-MB-436, CAL51, and HCC1143) and HER2+ (JIMT-1 and HCC1954) breast cancer cell lines at lower doses compared with luminal A (MCF-7, T-47D, and ZR-75-1) and luminal B (BT-474) breast cancer cell lines. Similarly, a significantly lower average colony number of JIMT-1 cells was seen upon treatment with BO-264 for 12 days. Despite a relatively lower sensitivity to TACC3 inhibition in RT4 cells, BO-264 yielded the lowest IC₅₀ value in both models (two human urinary bladder cancer cell lines, RT112 and RT4) as compared with SPL-B and KHS101 (other TACC3 inhibitors), suggesting BO-264 might be a highly relevant therapeutic opportunity to target FGFR3–TACC3 fusion-harboring tumors. Moreover, BO-264 decreased ERK1/2 phosphorylation, which is a marker for activated FGFR signaling along with a strong mitotic arrest at minimum 10× lower doses than other TACC3 inhibitors, suggesting that BO-264 specifically blocks the function of FGFR3–TACC3 fusion protein. BO-264 exhibited a remarkable anticancer activity against more than 90% of the cell lines representing nine different subpanels with GI₅₀ values less than 1 μM. siTACC3-induced mitotic arrest, apoptosis, and DNA damage were fully recapitulated by BO-264 in a dose-dependent manner. Furthermore, treatment of JIMT-1 cells with BO-264 for 48 hours induced a prominent increase (from 4.1% to 45.6%) in the fraction of apoptotic cells^[1].