Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Oct 31;39(20):e71152.
doi: 10.1096/fj.202502614R.

A Dual CYP17A1/HDAC6 Inhibitor for Targeted Prostate Cancer Therapy

Affiliations

A Dual CYP17A1/HDAC6 Inhibitor for Targeted Prostate Cancer Therapy

Hoang Yen Tran et al. FASEB J. .

Abstract

Prostate cancer remains a leading cause of cancer-related deaths in men, with androgen receptor (AR) signaling playing a critical role in disease progression. Although CYP17A1 inhibitors effectively suppress androgen biosynthesis, treatment resistance frequently emerges through alternative AR activation pathways. Additionally, histone deacetylase 6 (HDAC6) is implicated in AR hypersensitivity and stabilization, further contributing to castration-resistant prostate cancer. Thus, targeting both CYP17A1 and HDAC6 presents a promising therapeutic approach. We developed MPT1A160, a dual CYP17A1/HDAC6 inhibitor, and evaluated its efficacy on prostate cancer cells and a xenograft model. CCK-8 viability, wound healing, transwell migration, colony formation assays, and cell cycle analysis were performed. Immunoblotting quantified AR splice variant ARv7, AKR1C3, and KLK3 protein abundance, whereas Ki-67 and TUNEL staining assessed proliferation and apoptosis in tumor sections. Mice received DMSO, abiraterone, or MPT1A160 intraperitoneal injections twice per week. In silico analysis was used to assess oncogene expression and mutation frequencies in prostate cancer patient cohorts. MPT1A160 significantly suppressed prostate cancer cell viability with lower IC50 values and demonstrated superior tumor growth suppression in the 22Rv1 xenograft model compared to abiraterone. RNA-seq analysis revealed that MPT1A160 downregulated key oncogenic pathways and metabolic processes. Furthermore, several MPT1A160-suppressed genes exhibited high mutation frequencies in prostate cancer, suggesting their potential role in therapy resistance. MPT1A160 exhibits potent anti-tumor effects by targeting both androgen biosynthesis and epigenetic regulation, offering a novel dual inhibition strategy for overcoming treatment resistance in prostate cancer.

Keywords: AR signaling; chemoresistance; dual CYP17A1/HDAC6 inhibition; epigenetic regulation; prostate cancer.

PubMed Disclaimer

References

    1. H. Sung, J. Ferlay, R. L. Siegel, et al., “Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries,” CA: A Cancer Journal for Clinicians 71, no. 3 (2021): 209–249.
    1. E. Nevedomskaya, S. J. Baumgart, and B. Haendler, “Recent Advances in Prostate Cancer Treatment and Drug Discovery,” International Journal of Molecular Sciences 19, no. 5 (2018): 1359.
    1. A. J. Burton, K. M. Tilling, J. M. Holly, et al., “Metabolic Imbalance and Prostate Cancer Progression,” International Journal of Molecular Epidemiology and Genetics 1, no. 4 (2010): 248–271.
    1. T. K. Le, Q. H. Duong, V. Baylot, et al., “Castration‐Resistant Prostate Cancer: From Uncovered Resistance Mechanisms to Current Treatments,” Cancers 15, no. 20 (2023): 5047.
    1. E. D. Crawford, A. Heidenreich, N. Lawrentschuk, et al., “Androgen‐Targeted Therapy in Men With Prostate Cancer: Evolving Practice and Future Considerations,” Prostate Cancer and Prostatic Diseases 22, no. 1 (2019): 24–38.

MeSH terms

LinkOut - more resources