TAS4464, a highly potent and selective inhibitor of NEDD8 activating enzyme, shows antitumor activity. NEDD8 activating enzyme (NAE) is an essential regulator of the NEDD8 conjugation pathway. The ubiquitin-like modifier NEDD8 controls the stability and activity of its target proteins via a conjugation cascade (the neddylation pathway). NAE controls the degradation of many proteins with important roles in cell-cycle progression, DNA damage, and stress responses. NAE also regulates cancer cell growth and survival through activation of cullin-RING ubiquitin ligase complexes (CRLs). In the present study, reaserchers describe the preclinical profile of a novel, highly potent and selective NAE inhibitor TAS4464. Particularly, TAS4464 selectively inhibits NAE relative to the other E1s ubiquitin activating enzyme (UAE) and SUMO activating enzyme (SAE). Moreover, TAS4464 treatment inhibits cullin neddylation and subsequently induces the accumulation of CRL substrates such as CDT1, p27, and phosphorylated IκBα in human cancer cell lines. TAS4464 is highly potent with widespread antiproliferative activity not only for cancer cell lines but also patient derived tumor cells. TAS4464 shows prolonged target inhibition in human tumor xenograft mouse models. weekly or twice a week TAS4464 administration leads to prominent antitumor activity in multiple human tumor xenograft mouse models including both hematologic and solid tumors without marked weight loss. As a conclusion, TAS4464 is a potent and highly selective NAE inhibitor, showing superior antitumor activity with prolonged target inhibition. It is, therefore, a promising agent for the treatment of a variety of tumors including both hematologic and solid tumors.