Advancements in Androgen Receptor Inhibition: The Potential of Proxalutamide (GT0918) in Treating Prostate and Breast Cancers

The abstract discusses the role of androgen receptor (AR) in prostate cancer and the development of new treatments. Elevated AR expression or mutations lead to resistance against first-generation AR antagonists, which is a significant factor in the progression of castration-resistant prostate cancer (CRPC). MDV3100, a potent AR antagonist, has shown effectiveness in treating CRPC and is FDA-approved. However, there are concerns about CNS side effects and resistance to MDV3100.

Suzhou Kintor has developed a compound called Proxalutamide (GT0918), which is a strong AR antagonist that can reduce AR protein levels in prostate cancer cells. GT0918 has been shown to be more effective than Bicalutamide and MDV3100 in inhibiting androgen binding and blocking AR function in gene transcription. It also prevents androgen-stimulated AR translocation to the cell nuclei, blocking DNA binding and oncogenic signaling. GT0918 induces AR down regulation, which could be beneficial against CRPC resistant to current treatments. It has demonstrated potent inhibition of both hormone-sensitive and CRPC cell proliferation and also inhibits AR-positive breast cancer cell growth, while being selective for the AR pathway.

In animal models, GT0918 has shown promising anti-tumor efficacy with a lower effective drug exposure than MDV3100. It has an optimized ADME profile for once-daily dosing and has undergone IND-enabling GLP toxicology studies, showing good tolerance with minimal safety concerns. No seizures were observed in safety studies. An IND application has been submitted for a Phase I clinical trial to evaluate GT0918 as a selective AR pathway inhibitor.

The study is cited in the Proceedings of the 105th Annual Meeting of the American Association for Cancer Research, with details provided for reference.