2. Academic Validation
  3. A novel cereblon modulator for targeted protein degradation

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

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: 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, University of Science and Technology, Daejeon, 34113, Republic of Korea. Electronic address: jhoonkim@kribb.re.kr.
  • 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: jyhwang@krict.re.kr.
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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