2. Academic Validation
  3. Discovery and biological evaluation of darolutamide derivatives as inhibitors and down-regulators of wild-type AR and the mutants

Discovery and biological evaluation of darolutamide derivatives as inhibitors and down-regulators of wild-type AR and the mutants

  • Eur J Med Chem. 2019 Nov 15:182:111608. doi: 10.1016/j.ejmech.2019.111608.
Jiang Yu 1,  Peiting Zhou 1,  Mingxing Hu 1,  Liuqing Yang 2,  Guoyi Yan 3,  Ruixue Xu 1,  Yufang Deng 1,  Xinghai Li 4,  Yuanwei Chen 5
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 Department of Pharmacy, Shanxi Medical University, Taiyuan, Xinjian Road 56, 030001, China.
  • 3 Department of Hepatobiliary Pancreatic Surgery, Henan Province People's Hospital, Zhengzhou, 450003, China.
  • 4 Hinova Pharmaceuticals Inc, 4th Floor, Building RongYao A, No. 5, Keyuan South Road, Chengdu, 610041, China.
  • 5 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: ywchen@scu.edu.cn.
PMID: 31437779 DOI: 10.1016/j.ejmech.2019.111608
Abstract

Androgen Receptor (AR) has been a target of prostate Cancer (PC) for nearly six decades. Recently, downregulating or degrading AR and the mutants especially the splice variant 7 (AR-V7) lacking ligand binding domain (LBD) emerged as an advantageous therapeutic approach to overcome drug resistance. Here, the structural modification of darolutamide resulted in the discovery of dual-action AR inhibitors and down-regulators. Unlike Other traditional AR antagonists targeting the AR-LBD, compounds 4k and 4b not only inhibit the activities of wt-AR and AR-F876L mutant but also downregulate the protein expression of full-length (AR-full) and AR variant 7 (AR-V7) at mRNA level. In cell proliferation assays, compounds 4k and 4b exhibited better antiproliferative activities than darolutamide and enzalutamide against AR-V7-positive 22Rv1 cells and VCaP cells. In addition, 4k demonstrated better antitumor activity than clinically used enzalutamide in castration-resistant VCaP xenograft model. Collectively, combining the activities of AR inhibition and downregulation, compound 4k is proposed as an advantageous lead compound to disrupt AR signaling and overcome resistance.

Keywords

Androgen receptor down-regulators; Androgen receptor inhibitors; Castration-resistant prostate cancer; Darolutamide derivatives; F876L mutant.

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