With an increasing morbidity and mortality, the prostate cancer has threatened the survival and life quality of males in both developed and developing countries, such US and China. Castration or androgen disruption was the common treatment for prostate cancer patients. However, the disease usually processed to the late stage when diagnosed, the Castrated Resistant Prostate Cancer (CRPC), which was AR (androgen receptor) dependent. Therefore, drugs targeting the AR signaling pathway might be of great clinical significance.
In order to develop treatment against CRPC based on Enzalutamide proved by FDA in 2012, yet with less drug resistance, we have developed and evaluated the drug efficacy of our novel drug HC1119.
Influence of HC1119 on survival and apoptosis of AR-expressing cells, on AR trans-localization, and affinity to AR were tested. Effect of HC1119 on tumor growth and dose responses was evaluated in the SCID murine xenograft model.
Our studies indicated that HC1119 exhibited similar or better potential as Enzalutamide in vitro. HC1119 inhibited proliferation of LNCaP-AR cells (LNCaP cells with AR overexpression) with an IC50 of 85 nM. Incubation of HC1119 with VCaP cells induced cell apoptosis to the similar level as Enzalutamide. Besides, it also promoted nucleus trans-localization of AR.
As the first and probably only organization which was able to develop the CRPC SCID xenograft model in China, we have evaluated the efficacy of HC1119 in vivo. Our studies indicated that low, medium and high dosages of HC1119 prohibited tumor growth in the CRPC murine models, and the T/C ratio of mice treated with high dose of HC1119 was nearly 10%. Lastly, our PK studies indicated that the bioactivity of HC1119 was better than Enzalutamide in rats and dogs.
We have provided strong evidence for the anti-CRPC potential of HC1119 both in vitro and in vivo.