A novel cereblon modulator for targeted protein degradation.

Adaptor Proteins, Signal Transducing Animals Cell Line, Tumor Female Humans Immunologic Factors / chemical synthesis Mice Peptide Hydrolases / metabolism Piperidones / chemical synthesis Proteolysis / drug effects Ubiquitin-Protein Ligases Xenograft Model Antitumor Assays
BET CRBN IMiDs PROTAC

Journal

European journal of medicinal chemistry
ISSN: 1768-3254
Titre abrégé: Eur J Med Chem
Pays: France
ID NLM: 0420510

Informations de publication

Date de publication:
15 Mar 2019
Historique:
received: 07 11 2018
revised: 19 12 2018
accepted: 10 01 2019
pubmed: 27 1 2019
medline: 6 3 2019
entrez: 27 1 2019
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.ejmech.2019.01.023 PMID: 30684871
pubmed: 30684871
pii: S0223-5234(19)30033-9
doi: 10.1016/j.ejmech.2019.01.023
pii:
doi:

Substances chimiques

Adaptor Proteins, Signal Transducing 0
CRBN protein, human 0
Immunologic Factors 0
Piperidones 0
Ubiquitin-Protein Ligases EC 2.3.2.27
Peptide Hydrolases EC 3.4.-
glutarimide MV728O9612

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

65-74

Informations de copyright

Copyright © 2019 Elsevier Masson SAS. All rights reserved.

Auteurs

Sung Ah Kim (SA)

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.

Ara Go (A)

Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea.

Seung-Hyun Jo (SH)

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.

Sun Jun Park (SJ)

Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea.

Young Uk Jeon (YU)

Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea.

Ji Eun Kim (JE)

Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea.

Heung Kyoung Lee (HK)

Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea.

Chi Hoon Park (CH)

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.

Chong-Ock Lee (CO)

Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea.

Sung Goo Park (SG)

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.

Pilho Kim (P)

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.

Byoung Chul Park (BC)

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.

Sung Yun Cho (SY)

Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea.

Sunhong Kim (S)

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.

Jae Du Ha (JD)

Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon, 34114, Republic of Korea. Electronic address: jdha@krict.re.kr.

Jeong-Hoon Kim (JH)

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.

Jong Yeon Hwang (JY)

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.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines adaptatrices de la transduction du signal › A novel cereblon modulator for targeted...
questionsmedicales.fr › Eucaryotes › Animaux › A novel cereblon modulator for targeted...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › A novel cereblon modulator for targeted...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › A novel cereblon modulator for targeted...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Effets physiologiques des médicaments › Facteurs immunologiques › A novel cereblon modulator for targeted...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › A novel cereblon modulator for targeted...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Peptide hydrolases › A novel cereblon modulator for targeted...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Pipéridines › Pipéridones › A novel cereblon modulator for targeted...
questionsmedicales.fr › Métabolisme › Protéolyse › A novel cereblon modulator for targeted...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Ligases › Ubiquitin-protein ligase complexes › Ubiquitin-protein ligases › A novel cereblon modulator for targeted...
questionsmedicales.fr › Techniques d'investigation › Transplantation tumorale › Tests d'activité antitumorale sur modèle de xénogreffe › A novel cereblon modulator for targeted...