Identification of novel benzoyl hydrazine derivatives as activators of neddylation pathway to inhibit the tumor progression in vitro

Neddylation modification is frequently overexpressed in many types of human tumors. As a result, targeting neddylation pathway has been identified as viable anticancer therapeutic strategy. The NEDD8-activating enzyme (NAE) serves as a crucial role in a variety of cellular functions. Here, a new library of piperidine analogs was developed, produced and assessed for antiproliferative efficacy against A549, MGC-803, MCF-7KYSE-30 cell lines. The cell-based mechanistic studies showed that IIb-10 bearing the benzoyl hydrazine motif can selectively inhibit the Neddylation modification of Cullin1 and Cullin3 by inhibiting NEDD8 activase and then, leads to a dose-dependent reduction in the level of UBC12-NEDD8 complex via interacting with NAE1 directly. Cellular mechanisms elucidated that compound IIb-10 has the ability to halt the cell cycle of MGC-803 cells at G2/M phase and trigger apoptosis. Altogether, the hydrazide -linked piperidine derivatives may be promising candidates as lead compounds for the development of highly effective neddylation inhibitors.