synthesis and biological evaluation of novel anti-leukemia proteolysis-targeting chimeras in degradating inosine monophosphate dehydrogenase

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.