2. Academic Validation
  3. Design and characterization of cereblon-mediated androgen receptor proteolysis-targeting chimeras

Design and characterization of cereblon-mediated androgen receptor proteolysis-targeting chimeras

  • Eur J Med Chem. 2020 Dec 15;208:112769. doi: 10.1016/j.ejmech.2020.112769.
Akshay D Takwale 1,  Seung-Hyun Jo 2,  Yeong Uk Jeon 3,  Hyung Soo Kim 4,  Choong Hoon Shin 5,  Heung Kyoung Lee 3,  Sunjoo Ahn 3,  Chong Ock Lee 3,  Jae Du Ha 6,  Jeong-Hoon Kim 7,  Jong Yeon Hwang 8
Affiliations

Affiliations

  • 1 Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 305-606, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, Korea University of Science and Technology, Daejeon, 34113, Republic of Korea.
  • 2 Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea; Department of Functional Genomics, Korea University of Science and Technology, Daejeon, 34113, Republic of Korea.
  • 3 Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 305-606, Republic of Korea.
  • 4 Department of Chemistry, Korea Univeristy, Seoul, 02841, Republic of Korea.
  • 5 Department of Chemistry, Sogang Univeristy, Seoul, 04107, Republic of Korea.
  • 6 Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 305-606, Republic of Korea. Electronic address: jdha@krict.re.kr.
  • 7 Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea; Department of Functional Genomics, Korea University of Science and Technology, Daejeon, 34113, Republic of Korea. Electronic address: jhoonkim@kribb.re.kr.
  • 8 Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 305-606, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, Korea University of Science and Technology, Daejeon, 34113, Republic of Korea. Electronic address: jyhwang@krict.re.kr.
PMID: 32961381 DOI: 10.1016/j.ejmech.2020.112769
Abstract

Proteolysis-targeting chimera (PROTAC)-mediated protein degradation is a rapidly emerging therapeutic intervention that induces the degradation of targeted proteins. Herein, we report the design and biological evaluation of a series of Androgen Receptor (AR) PROTAC degraders for the treatment of metastatic castration-resistant prostate Cancer. Predominantly, instead of thalidomide, we utilized the TD-106 scaffold, a novel Cereblon (CRBN) binder that was identified in our previous study. Our results suggest that the linker position in the TD-106 CRBN binder is critical for the efficiency of AR degradation. The compounds attached to the 6-position of TD-106 promoted better degradation of AR than those at the 5- and 7-positions. Among the synthesized AR PROTACs, the representative degrader 33c (TD-802) effectively induced AR protein degradation, with a degradation concentration 50% of 12.5 nM and a maximum degradation of 93% in LNCaP prostate Cancer cells. Additionally, most AR PROTAC degraders, including TD-802, displayed good liver microsomal stability and in vivo pharmacokinetic properties. Finally, we showed that TD-802 effectively inhibited tumor growth in an in vivo xenograft study.

Keywords

Androgen receptor; Cereblon; Prostate cancer; Proteolysis targeting chimera; TD-106.

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