UPDATE: AO-252, a New First-in-Class Brain-Penetrating TACC3 Inhibitor for Prostate Cancer

A new drug called AO-252, an oral inhibitor of TACC3, is now in phase 1 trials specifically testing it against prostate cancer among other solid tumors. It smartly blocks TACC3’s key partnerships with proteins like KIFC1, clathrin, BRCA1, and others, triggering mitotic disasters and halting growth in both lab models and early patients (some saw tumors shrink by 22% on low doses with no major side effects yet.)​

TACC3 is a protein that plays a big role in making prostate cancer more aggressive and harder to treat. Studies show it’s often overexpressed in advanced cases, linking it directly to shorter disease-free survival and worse outcomes for patients. High levels mean tumors grow faster, spread easier, and resist therapies better.​

This protein fuels cancer growth through several pathways. It ramps up Wnt/β-catenin signaling to boost cell division and stem-like traits, helps cluster extra centrosomes during mitosis to avoid cell death, and even blocks primary cilia that normally keep cells in check. In metastatic and castration-resistant prostate cancer, TACC3 steps up to drive invasion, migration, and genomic chaos, making it a prime suspect for why some tumors keep coming back.​

Preclinical work shines in tough prostate models, including brain metastases, where AO-252 caused full regressions, especially in p53-mutated or centrosome-heavy tumors. The trial’s expanding to prostate cohorts, with clean safety so far and plans for bigger studies soon, hinting at real potential to tackle resistant cases where options are slim.​

Overall, targeting TACC3 with AO-252 could change the game for aggressive prostate cancer by hitting multiple weak spots at once, offering hope beyond standard hormone treatments.

Clinical trial.