BSJ-04-132 is a Selective Ribociclib-Based CDK4 Degrader (PROTAC)
Posted On 2020-10-24
Targeted protein degradation induced by PROTAC has become a new therapeutic strategy in drug development. Besides, PROTAC has two covalently linked protein binding molecules. One can bind E3 ubiquitin ligases and the other can bind to the target protein to be degraded. Moreover, the recruitment of E3 ligase to target protein leads to the ubiquitination of proteasome and subsequent degradation of the target protein. Furthermore, PROTAC only needs to combine its target with high selectivity. CDKs are relatively small proteins with molecular weights ranging from 34 to 40 kDa and contain only kinase domains. Nonetheless, they exist in all known eukaryotes, and their regulatory functions in the cell cycle are evolutionarily conservative. The Ser/Thr kinase component of cyclin D-CDK4 complex phosphorylates and inhibits members of the retinoblastoma protein family. It regulates the cell cycle during the G1/S transition. BSJ-04-132 is a potent and selective Ribociclib-based CDK4 degrader (PROTAC).
BSJ-04-132 is a potent and selective Ribociclib-based CDK4 degrader (PROTAC)
How does brd3308 work on the target? Let’s study it together. In the beginning, BSJ-04-132 is a selective Ribociclib-based CDK4 degrader (PROTAC), with IC50s of 50.6 nM and 30 nM for CDK4/D1 and CDK6/D1, respectively. Meanwhile, BSJ-04-132 does not induce CDK6 and IKZF1/3 degradation. Particularly, BSJ-04-132 has anti-cancer activity. In the second place, BSJ-04-132 only results in the degradation of CDK4 in WT cells, not CDK6 and IKZF1/3 with 0.1-5 μM for 4 hours. In cells treated with BSJ-04-132, CDK4 did not meet our minimum 2-fold change. But its level was reduced to a greater extent than those of CDK6, IKZF1, and IKZF3. Finally, the treatment of Molt4 cells with BSJ-03-123 resulted in the loss of CDK6, but not CDK4 or IKZF1/3.
All in all, BSJ-04-132 is a potent and selective Ribociclib-based CDK4 degrader (PROTAC) with anti-cancer activity.
Baishan Jiang, et al. Angew Chem Int Ed Engl. 2019 May 6;58(19):6321-6326.