Abstract
NEDDylation, a post-translational modification through three-step enzymatic cascades, plays crucial roles in the regulation of diverse biological processes. NEDD8-activating enzyme (NAE) as the only activation enzyme in the NEDDylation modification has become an attractive target to develop anticancer drugs. To date, numerous inhibitors or agonists targeting NAE have been developed. Among them, covalent NAE inhibitors such as MLN4924 and TAS4464 currently entered into clinical trials for cancer therapy, particularly for hematological tumors. This review explains the relationships between NEDDylation and cancers, structural characteristics of NAE and multistep mechanisms of NEDD8 activation by NAE. 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.
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Background
Neuronal precursor cell-expressed developmentally down-regulated protein 8 (NEDD8) shares about 60% of the amino acids with ubiquitin, which covalently binds to substrate proteins by generating an isopeptide chain between the lysine residue of substrates and the glycine residue of NEDD8 [1,2,3,4,5]. NEDDylation is a biochemical process of post-translational modification that conjugates NEDD8 to substrate proteins through the successive enzymatic cascades [6,7,8,9,10]. In the initial stage of NEDDylation, the precursor of NEDD8 is hydrolyzed to mature NEDD8 by the precursor processing enzymes [11,12,13,14]. Next, the mature NEDD8 is activated in the presence of adenosine triphosphate (ATP) by the E1 NEDD8-activating enzyme (NAE) consisting of amyloid protein-binding protein 1 (APPBP1) and ubiquitin-like modifier activating enzyme 3 (UBA3) [15,16,17]. Then, the activated NEDD8 is transferred to NEDD8-conjugating enzyme E2s (UBC12 and UBE2F) via a trans-thiolation process [18, Not applicable. NEDD8-activating enzyme Neuronal precursor cell-expressed developmentally down-regulated protein 8 Adenosine triphosphate Amyloid protein-binding protein 1 Ubiquitin-like modifier activating enzyme 3 Cullin-RING ligases Active adenylation domain Inactive adenylation domain Catalytic cysteine Ubiquitin fold domain Acute myeloid leukemia Half-life Area under the plasma concentration–time curve Volume of distribution Clearance Peak concentration I-kappa-B-alpha Adenosine 5′-monophosphate TNF-related apoptosis-inducing ligand Head and neck squamous cell carcinoma Tricarboxylic acid cycle Oxidative phosphorylation system Tumor microenvironment Nuclear factor κB Multiple myeloma Hematologic malignancies Hodgkin lymphoma Myelodysplastic syndromes Acute lymphoblastic leukemia Chronic lymphocytic leukemia Chronic myelomonocytic leukemia Myeloproliferative neoplasm Myelodysplastic syndromes Chromosome ten Protein kinase B Pyruvate kinase isoform M2 Interleukin-17A Zubiete-Franco I, Fernández-Tussy P, Barbier-Torres L, Simon J, Fernández-Ramos D, Lopitz-Otsoa F, et al. 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MLN4924 inhibits hedgehog signaling pathway and activates autophagy to alleviate mouse laser-induced choroidal neovascularization lesion. Biomed Pharmacother. 2020;130:110654. Not applicable. This work was supported by the Fundamental Research Funds for the Central Universities [Grant No. 2022-JYB-XJSJJ025 to Dong-Jun Fu]. This work was also funded by China Postdoctoral Science Foundation [Grant No. 2020M670239 to Dong-Jun Fu]. D-JF collected the references, designed the outline, prepared all figures and wrote the manuscript. TW offered important guidance of manuscript reviewing and editing. D-JF and TW approved the final manuscript. Not applicable. Not applicable. The authors declare that they have no competing interests. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. 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The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Fu, DJ., Wang, T. Targeting NEDD8-activating enzyme for cancer therapy: developments, clinical trials, challenges and future research directions.
J Hematol Oncol 16, 87 (2023). https://doi.org/10.1186/s13045-023-01485-7 Received: Accepted: Published: DOI: https://doi.org/10.1186/s13045-023-01485-7Availability of data and materials
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