2. Academic Validation
  3. Metabolically stable diphenylamine derivatives suppress androgen receptor and BET protein in prostate cancer

Metabolically stable diphenylamine derivatives suppress androgen receptor and BET protein in prostate cancer

  • Biochem Pharmacol. 2020 Jul;177:113946. doi: 10.1016/j.bcp.2020.113946.
Jiang Yu 1,  Peiting Zhou 1,  Wu Du 2,  Ruixue Xu 1,  Guoyi Yan 3,  Yufang Deng 1,  Xinghai Li 2,  Yuanwei Chen 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
  • 2 Hinova Pharmaceuticals Inc., 4th Floor, Building RongYao A, No. 5, Keyuan South Road, Chengdu 610041, China.
  • 3 Department of Hepatobiliary Pancreatic Surgery, Henan Province People's Hospital, Zhengzhou 450003, China.
  • 4 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China; Hinova Pharmaceuticals Inc., 4th Floor, Building RongYao A, No. 5, Keyuan South Road, Chengdu 610041, China. Electronic address: [email protected].
PMID: 32247852 DOI: 10.1016/j.bcp.2020.113946
Abstract

Androgen Receptor (AR) is a crucial driver of prostate Cancer (PC). AR-relevant resistance remains a major challenge in castration-resistant prostate Cancer (CRPC). Bromodomain and extra-terminal domain (BET) family are critical AR coregulators. Here, we developed several diphenylamine derivatives and identified compound 7d that disrupted the functions of AR and BET family in prostate Cancer and exhibited favorable metabolic stability in vitro and high drug exposure in vivo. We showed 7d not only bound to AR, suppressed transactivation of wild-type AR (wt-AR) and the mutant that mediates Enzalutamide resistance, but also reduced c-Myc protein expression through BET inhibition. In addition, 7d inhibited the proliferation of AR-positive PC cells with favorable selectivity and suppressed AR-V7-expressing VCaP and 22Rv1 xenografts growth in vivo. Collectively, these results indicate the potential of lead compound 7d as an orally available AR and BET inhibitor to treat CRPC and overcome antiandrogen resistance.

Keywords

Androgen receptor; Antiandrogen resistance; Bromodomain and extra-terminal domain; Castration-resistant prostate cancer; Diphenylamine derivatives.

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