Advancements in Targeted Therapies: Next-Generation AR NTD Inhibitors for Castration-Resistant Prostate Cancer

The androgen receptor (AR) remains a key driver in castration-resistant prostate cancer (CRPC), necessitating the development of new therapies to overcome resistance to anti-androgens. A Phase I clinical trial of the AR NTD inhibitor EPI-506 showed some efficacy in patients with anti-androgen resistant metastatic CRPC, but the effects were limited, highlighting a need for more potent and stable NTD inhibitors.

A new series of NTD transcriptional inhibitors, termed Anitens, have been developed, with EPI-7170 and EPI-7245 exemplifying this class. These compounds have demonstrated significantly improved potency and metabolic stability, along with enhanced pharmaceutical properties, effectively targeting anti-androgen resistant prostate cancer in both in vitro and preclinical models.

The development of these next-generation Anitens involved optimizing chemical structures for increased potency and metabolic stability, as measured by cellular assays, in vivo tests, and ADME assays. The on-target activity and selectivity were refined through various cellular experiments.

Results indicate a substantial increase in potency for these Anitens, with IC50 values ranging from 0.5-1 uM, compared to 10 uM for the first-generation EPI-002. The specificity of Aniten AR inhibition for the NTD was confirmed, with no binding to the LBD and inhibition of AR-V7-driven transcription in the LNCaP95 model. Proliferation assays confirmed AR-dependent activity, and the antiproliferative effects correlated with the inhibition of a subset of AR-driven genes. In vivo studies in mice bearing LNCaP tumors showed significant decreases in serum PSA levels and tumor growth inhibition.

Subsequent chemistry efforts led to the creation of EPI-7245 and other next-generation Anitens with IC50 values below 500 nM. These compounds displayed favorable ADME and PK profiles, including a half-life of approximately 8 hours in mice and predicted low human clearance.

In conclusion, the next-generation Aniten compounds have shown significant improvements over the first-generation clinical compound EPI-002, with retained NTD specificity and enhanced potency and metabolic stability. These advancements position the new Anitens as promising candidates for AR targeted therapeutics in both hormone-sensitive and castration-resistant prostate cancer.