2. Academic Validation
  3. α-naphthoflavone-derived cytochrome P450 (CYP)1B1 degraders specific for sensitizing CYP1B1-mediated drug resistance to prostate cancer DU145: Structure activity relationship

α-naphthoflavone-derived cytochrome P450 (CYP)1B1 degraders specific for sensitizing CYP1B1-mediated drug resistance to prostate cancer DU145: Structure activity relationship

  • Bioorg Chem. 2021 Nov;116:105295. doi: 10.1016/j.bioorg.2021.105295.
Peng Chen 1,  Shaobing Wang 2,  Chenyang Cao 3,  Wenchong Ye 3,  Meizhu Wang 3,  Cui Zhou 3,  Wenming Chen 4,  Xu Zhang 5,  Keyu Zhang 6,  Wen Zhou 7
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, University town, Waihuan Rd., Panyu, Guangzhou, 510006, China; Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 200241, Shanghai, China.
  • 2 School of Pharmaceutical Sciences, South-Central University for nationalities, Wuhan, 430074, China.
  • 3 School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, University town, Waihuan Rd., Panyu, Guangzhou, 510006, China.
  • 4 Department of Pharmaceutical Production Center ＆TCM and Ethnomedicine Development International Laboratory, The First Hospital of Hunan University of Chinese Medicine, 95, Shaoshan Rd, Changsha, Hunan, 41007, China.
  • 5 College of Forestry and Landscape Architecture, South China Agricultural University, 510642, China. Electronic address: zhangxu@126.com.
  • 6 Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 200241, Shanghai, China; Key Laboratory of Veterinary Chemical Drugs and Pharmaceutics, Ministry of Agriculture and Rural Affairs, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, P.R. China. Electronic address: zcole@shvri.ac.cn.
  • 7 Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, 200241, Shanghai, China; Key Laboratory of Veterinary Chemical Drugs and Pharmaceutics, Ministry of Agriculture and Rural Affairs, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, P.R. China. Electronic address: zhouwen60@126.com.
PMID: 34455300 DOI: 10.1016/j.bioorg.2021.105295
Abstract

We previously discovered extrahepatic Cytochrome P450 1B1 (CYP1B1) degraders able to overcome drug resistance toward docetaxel using a PROTACs technology, however, the underexplored structure activity relationships and poor water solubility posed a major hurdle in the development of CYP1B1 degraders. Herein, continuous efforts are made to develop more promising α-naphthoflavone (ANF)-derived chimeras for degrading CYP1B1. Guided by the strongest ANF-derived CYP1B1 degrader 3a we ever reported, 17 ANF analogues are designed and synthesized to evaluate the CYP1B1 degradation and resultant resistance reversal. In degrading CYP1B1 and sensitizing drug resistance, 4d with a 1, 5-cis triazole coupling mode at (C3') of B ring of ANF exhibited the similar potency as 3a carrying a 1, 4-trans triazole fragment at (C4') of B ring, but more obvious selectivity of 4d toward CYP1B1 over CYP1A2 is observed. When an oxygen was inserted into the linker of 4d, 4f demonstrated better water solubility, a more potent ability in degrading CYP1B1 and reversing drug resistance, and a promising selectivity. Collectively, a substitution position, an alkyne-azide cyclization and a liker type significantly affect the ability of ANF-thalidomide conjugates in eliminating drug resistance of CYP1B1-expressing DU145 (DU145/CY) cells to docetaxel via targeted CYP1B1 degradation.

Keywords

α-Naphthoflavone-based CYP1B1 degrader.

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