A novel cereblon modulator for targeted protein degradation

  • Eur J Med Chem. 2019 Mar 15;166:65-74. doi: 10.1016/j.ejmech.2019.01.023.
Sung Ah Kim  1 ,  Ara Go  2 ,  Seung-Hyun Jo  1 ,  Sun Jun Park  2 ,  Young Uk Jeon  2 ,  Ji Eun Kim  2 ,  Heung Kyoung Lee  2 ,  Chi Hoon Park  3 ,  Chong-Ock Lee  2 ,  Sung Goo Park  1 ,  Pilho Kim  3 ,  Byoung Chul Park  4 ,  Sung Yun Cho  2 ,  Sunhong Kim  5 ,  Jae Du Ha  6 ,  Jeong-Hoon Kim  7 ,  Jong Yeon Hwang  8
Affiliations
  • 1. Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea; Department of Functional Genomics, University of Science and Technology, Daejeon, 34113, Republic of Korea.
  • 2. Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea.
  • 3. Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, Daejeon, 34113, Republic of Korea.
  • 4. Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea; Department of Bio-Analytical Science, University of Science and Technology, Daejeon, 34113, Republic of Korea.
  • 5. Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea; Department of Biomolecular Science, University of Science and Technology, Daejeon, 34113, Republic of Korea.
  • 6. Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea. Electronic address: [email protected].
  • 7. Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea; Department of Functional Genomics, University of Science and Technology, Daejeon, 34113, Republic of Korea. Electronic address: [email protected].
  • 8. Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, Daejeon, 34113, Republic of Korea. Electronic address: [email protected].
PMID: 30684871 DOI: 10.1016/j.ejmech.2019.01.023
Abstract

Immunomodulatory drugs (IMiDs) exert anti-myeloma activity by binding to the protein Cereblon (CRBN) and subsequently degrading IKZF1/3. Recently, their ability to recruit E3 ubiquitin Ligase has been used in the proteolysis targeting chimera (PROTAC) technology. Herein, we design and synthesize a novel IMiD analog TD-106 that induces the degradation of IKZF1/3 and inhibits the proliferation of Multiple Myeloma cells in vitro as well as in vivo. Moreover, we demonstrate that TD-428, which comprises TD-106 linked to a BET Inhibitor, JQ1 efficiently induce BET protein degradation in the Prostate Cancer cell line 22Rv1. Consequently, cell proliferation is inhibited due to suppressed c-Myc transcription. These results, therefore, firmly suggest that the newly synthesized IMiD analog, TD-106, is a novel CRBN modulator that can be used for targeted protein degradation.

Keywords
BET; CRBN; IMiDs; PROTAC.
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