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

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Abstract

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.

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Acknowledgements

This work was supported by Henan science and technology key project (No. 202102310148).

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Author notes

  1. These authors contributed equally: Xuan Wang, Sumeng Guan

Authors and Affiliations

  1. School of Pharmaceutical Science, Zhengzhou University, Zhengzhou, 450001, Henan, China

    Xuan Wang, Sumeng Guan, Zunming Tian, Mei Zhao, Mengyu Li, Hua Yang, Ling Zhu & Moran Sun

  2. Key Laboratory of Advanced Drug Preparation Technologies (Zhengzhou University), Ministry of Education of China, Zhengzhou, 450001, China

    Xuan Wang, Sumeng Guan, Zunming Tian, Mei Zhao, Mengyu Li, Hua Yang, Ling Zhu & Moran Sun

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  1. Xuan Wang
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Correspondence to Moran Sun.

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Wang, X., Guan, S., Tian, Z. et al. Identification of novel benzoyl hydrazine derivatives as activators of neddylation pathway to inhibit the tumor progression in vitro. Med Chem Res 33, 504–517 (2024). https://doi.org/10.1007/s00044-024-03193-4

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  • DOI: https://doi.org/10.1007/s00044-024-03193-4

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