A novel cereblon modulator for targeted protein degradation.
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.
Mesh Terms:
Animals, Cell Line, Tumor, Female, Humans, Immunologic Factors, Mice, Peptide Hydrolases, Piperidones, Proteolysis, Xenograft Model Antitumor Assays
Animals, Cell Line, Tumor, Female, Humans, Immunologic Factors, Mice, Peptide Hydrolases, Piperidones, Proteolysis, Xenograft Model Antitumor Assays
Eur J Med Chem
Date: Mar. 15, 2019
PubMed ID: 30684871
View in: Pubmed Google Scholar
Download Curated Data For This Publication
220042
Switch View:
- Chemical Interactions 6