A novel cereblon modulator for targeted protein degradation

다국어 초록 (Multilingual Abstract)

<P><B>Abstract</B></P> <P>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 <I>in vitro</I> as well as <I>in vivo</I>. 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.</P> <P><B>Highlights</B></P> <P> <UL> <LI> We design and synthesize a novel IMiD analog. </LI> <LI> TD-106 induces the degradation of IKZF1/3 and inhibits the proliferation of multiple myeloma cells. </LI> <LI> BET PROTAC with TD-106 efficiently induces the degradation of BET proteins. </LI> <LI> TD-106 as a novel CRBN modulator can be used for targeted protein degradation. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>