Research Paper Volume 13, Issue 5 pp 6982—6998

Discovery of a novel AR/HDAC6 dual inhibitor for prostate cancer treatment

Maojun Zhou1, *, , Hao Zheng2, *, , Yubin Li1, *, , Huichao Huang1, , Xiaoli Min1, , Shuyan Dai1, , Wenqiang Zhou3, , Zhuchu Chen1, , Guangyu Xu2, , Yongheng Chen1, ,

  • 1 Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, National Center for Geriatrics Clinical Research, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
  • 2 Key Laboratory of Chemical Biology and Traditional Chinese Medicine, Ministry of Educational of China, Key Laboratory of the Assembly and Application of Organic Functional Molecules of Hunan Province, Hunan Normal University, Changsha 410081, Hunan, China
  • 3 Zeta Pharma, Changsha 410000, Hunan, China
* Equal contribution

Received: June 15, 2020       Accepted: December 23, 2020       Published: February 17, 2021
How to Cite

Copyright: © 2021 Zhou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Androgen receptor (AR) and histone deacetylase 6 (HDAC6) are important targets for cancer therapy. Given that both AR antagonists and HDAC6 inhibitors modulate AR signaling, a novel AR/HDAC6 dual inhibitor is investigated for its anticancer effects in castration-resistant prostate cancer (CRPC). Zeta55 inhibits nuclear translocation of AR and suppresses androgen-induced PSA and TMPRSS2 expression. Meanwhile, Zeta55 selectively inhibits HDAC6 activity, leading to AR degradation. Zeta55 reduces the growth of AR-overexpressing VCaP prostate cancer cells both in vitro and in a CRPC xenograft model. These results provide preclinical proof of principle for Zeta55 as a promising therapeutic in prostate cancer treatment.


AR: Androgen receptor; HDACs: histone deacetylases; CRPC: castration-resistant prostate cancer; HDACi: histone deacetylase inhibitors; HSP90: heat shock protein 90; DHT: dihydrotestosterone; DMSO: dimethyl sulfoxide; DMEM: Dulbecco's modified Eagle's medium; PSA: Prostate-specific antigen; DAPI: 4’,6-diamidine-2’-phenylindole.