Targeting TACC3: Unveiling the Potential of a Novel Inhibitor in Breast Cancer Therapy

Transforming Acidic Coiled-Coil Containing Protein 3 (TACC3), a microtubule-associated protein, plays a crucial role in mitotic spindle formation and chromosomal segregation, thus maintaining microtubule stability. Its frequent amplification or mutation in various cancers suggests its potential as a therapeutic target. Previous studies have shown that TACC3 suppression can lead to mitotic spindle issues and cell death. Although small molecule inhibitors like KHS101 and SPL-B have shown efficacy in reducing tumor growth in certain cancer types, they have not advanced to clinical trials possibly due to stability or potency issues.

In an effort to discover a more potent TACC3 inhibitor, a strategy combining rational drug design and screening was employed. This involved modifying existing TACC3 inhibitors by replacing certain functional groups with isosteric equivalents to enhance their potency and drug-like characteristics. The newly synthesized compounds were then evaluated for their ability to inhibit the growth of various breast cancer cell lines and compared with the effects of TACC3 siRNAs on cellular processes.

BO-264 emerged as a highly effective TACC3 inhibitor, capable of killing different breast cancer cell subtypes at nanomolar concentrations. It outperformed existing inhibitors in terms of inhibiting mitotic progression, DNA repair, and enhancing cellular viability. When administered orally, BO-264 effectively suppressed tumor growth in breast cancer xenografts without apparent toxicity. Its specificity for TACC3 was confirmed through kinome profiling and binding assays.

Currently, ongoing research is focused on examining the pharmacokinetics, pharmacodynamics, and organ toxicity of BO-264, as well as characterizing the molecular mechanisms behind its anti-tumor effects. The findings indicate that BO-264 could be a specific TACC3 inhibitor that induces mitotic arrest, DNA damage, and apoptosis in breast cancer cells, suggesting its potential as a novel therapeutic agent for breast cancer treatment. Given TACC3's significance as a biomarker and disease progression driver, BO-264 holds promise as a new approach in combating breast cancer.