Synthesis and Biological Evaluation of Novel Anti-leukemia Proteolysis-Targeting Chimeras in Degradating Inosine Monophosphate Dehydrogenase.

Abstract

Background: Proteolysis-targeting chimera (PROTAC) is a bifunctional molecule comprising a ligand to recognize the targeted protein to be degraded.

Objectives: To use the advantages of the PROTAC technique, we have synthesized novel compounds to degrade inosine monophosphate dehydrogenase (IMPDH) by the proteasome system.

Methods: We describe the synthesis of new PROTACs based on a combination of mycophenolic acid (MPA) as the potent IMPDH inhibitor and pomalidomide as a ligand of E3 ubiquitin ligase via linkers formed from Cu(I)-catalyzed cycloaddition reaction.

Results: All synthesized compounds were investigated against Jurkat cells as acute T-cell leukemia and were potent apoptosis inducers at 50 nM.

Conclusion: The effect of compound 2 in 0.05 μM on IMPDH degradation can be almost prevented by competition with bortezomib as the proteasome inhibitor at 0.1 and 0.5 μM.