TAS4464

Finally, the results of the in vitro and in vivo experiments revealed that the NEDDylation inhibitor TAS4464 could inhibit PCNA NEDDylation to decrease PCNA protein expression, thereby suppressing HCC cell growth...This study provides a new perspective on the specific mechanism of HCC growth. It expands our understanding of the role of NEDDylation in the regulation of substrate proteins and their functions.

Among them, covalent NAE inhibitors such as MLN4924 and TAS4464 currently entered into clinical trials for cancer therapy, particularly for hematological tumors. In addition, the potential approaches to discover NAE inhibitors and detailed pharmacological mechanisms of NAE inhibitors in the clinical stage are explored in depth. Importantly, we reasonably investigate the challenges of NAE inhibitors for cancer therapy and possible development directions of NAE-targeting drugs in the future.

TAS4464 activated both caspase-8 and caspase-9 along with an increase in NOXA and a decrease in c-FLIP, resulting in complete tumor remission in a human AML xenograft model. These findings suggest that NAE inhibition leads to anti-AML activity via a novel c-Myc-dependent apoptosis induction mechanism.