Blood-Brain Barrier (BBB)-Penetrable Androgen Receptor (AR) Degrader as a Potential Therapeutic Agent for...

Androgen receptor (AR) contributes to the progression of glioblastoma (GBM), which is consistent with the sex difference in GBM, which has a higher incidence in males than in females. Therefore, targeting AR is a potential therapeutic approach for GBM treatment. However, AR mutation commonly occurs in GBM, which makes conventional AR antagonists less effective. AR degraders abolish AR at the protein level regardless of the mutation status of AR, which makes it a better strategy in GBM. Compound A is an analog of the cyclooxygenase-2 (COX-2) inhibitor Nimesulide. Mechanistically, compound A targets HSP27, disrupts the HSP27-AR complex, and thereby promotes AR degradation in GBM cells at 1 μM, leading to inhibition of AR-overexpressing GBM cell growth with IC₅₀s around 0.2 μM. In a GBM patient-derived cell line, DI318, compound A (1 μΜ) also significantly decreases AR protein levels. The compound significantly inhibits GBM xenograft growth at 20 mg/kg and does not cause toxicity in mice up to 200 mg/kg. Pharmacokinetic studies reveal that compound A has a half-life (t _1/2) of 3.11 h and a BBB penetration of 52%, which is even higher than the standard chemotherapy Temozolomide. These results suggest that the AR degrader has great potential as a novel GBM treatment.