Discovery of novel indole derivatives that inhibit NEDDylation and MAPK pathways against gastric cancer MGC803 cells.

A series of novel indole derivatives were synthesized and evaluated for their antiproliferative activity against three selected cancer cell lines (MGC803, EC-109 and PC-3). Among these analogues, 2-(5-methoxy-1H-indol-1-yl)-N-(4-methoxybenzyl)-N-(3,4,5-trimethoxyphenyl)acetamide (V7) showed the best inhibitory activity against MGC803 cells with an IC50 value of 1.59 µM. Cellular mechanisms elucidated that V7 inhibited colony formation, induced apoptosis and arrested cell cycle at G2/M phase. Importantly, indole analogue V7 inhibited NEDDylation pathway and MAPK pathway against MGC803 cells.

The Double-Edged Effects of MLN4924: Rethinking Anti-Cancer Drugs Targeting the Neddylation Pathway.

(1) Background: The neddylation pathway assumes a pivotal role in the initiation and progression of cancer. MLN4924, a potent small-molecule inhibitor of the NEDD8-activating enzyme (NAE), effectively intervenes in the early stages of the neddylation pathway. By instigating diverse cellular responses, such as senescence and apoptosis in cancer cells, MLN4924 also exerts regulatory effects on non-malignant cells within the tumor microenvironment (TME) and tumor virus-infected cells, thereby impeding the onset of tumors. Consequently, MLN4924 has been widely acknowledged as a potent anti-cancer drug. (2) Recent findings: Nevertheless, recent findings have illuminated additional facets of the neddylation pathway, revealing its active involvement in various biological processes detrimental to the survival of cancer cells. This newfound understanding underscores the dual role of MLN4924 in tumor therapy, characterized by both anti-cancer and pro-cancer effects. This dichotomy is herein referred to as the "double-edged effects" of MLN4924. This paper delves into the intricate relationship between the neddylation pathway and cancer, offering a mechanistic exploration and analysis of the causes underlying the double-edged effects of MLN4924-specifically, the accumulation of pro-cancer neddylation substrates. (3) Perspectives: Here, the objective is to furnish theoretical support and novel insights that can guide the development of next-generation anti-cancer drugs targeting the neddylation pathway.

Pevonedistat Suppresses Pancreatic Cancer Growth via Inactivation of the Neddylation Pathway.

BACKGROUND: The neddylation pathway is aberrantly overactivated in multiple human cancers and has been indicated as an effective target for anticancer therapy in clinical trials. We aimed to study whether the neddylation pathway is upregulated in pancreatic cancer and whether pevonedistat, a first-in-class anticancer agent specifically targeting this pathway, will suppress cancer tumorigenesis and progression. METHODS: We evaluated the expression pattern of neddylation pathway components in 179 pancreatic adenocarcinoma (PAAD) compared with 171 normal tissues from The Cancer Genome Atlas (TCGA) dataset and further assessed PAAD patient prognosis with high neddylation pathway expression via Gene Expression Profiling Interactive Analysis (GEPIA). We then analyzed malignant cancer phenotypes both in vitro and in vivo, as well as intrinsic molecular mechanisms upon pevonedistat treatment. RESULTS: We found that the neddylation pathway was hyperactivated in pancreatic cancer. Patients with high neddylation pathway expression exhibited worse prognoses. Pevonedistat significantly inhibited the cancer cell cycle, cell growth, and proliferation; increased cell apoptosis; and decreased cancer cell xenografts in a mouse model. Mechanistically, pevonedistat treatment and the siRNA knockdown neddylation pathway were able to remarkably induce the accumulation of Wee1, p27, and p21. Further mechanistic studies revealed that pevonedistat mainly impaired the ubiquitination level and delayed the protein degradation of Wee1, p27, and p21. CONCLUSIONS: Our results showed that pevonedistat targeted the overexpression of the neddylation pathway in pancreatic cancer to induce cell growth suppression by inducing the accumulation of the cell cycle regulators Wee1, p27, and p21, which provides sound evidence for the clinical trial of pevonedistat for pancreatic cancer therapy.

Neddylation pathway promotes myeloid-derived suppressor cell infiltration via NF-κB-mCXCL5 signaling in lung cancer.

Myeloid-derived suppressor cells (MDSCs), a population derived from immature myeloid progenitors, are present in the tumors of patients and highly protumorigenic. However, the molecular mechanisms regulating MDSC infiltration remain unclear. Neddylation pathway is overactivated in multiple cancers and has a significant role in tumor progression. We established a subcutaneous transplantation model of Lewis lung cancer in mice and showed that inactivation of neddylation pathway inhibits MDSC infiltration and impairs lung cancer growth. A high expression level of neuronal precursor cell-expressed developmentally downregulated protein 8 (NEDD8) is positively correlated with MDSC infiltration in human lung adenocarcinomas (LUADs). Moreover, inactivation of neddylation pathway inhibits the expression of murine CXCL5 (mCXCL5; human homolog CXCL6, hCXCL6), an important cytokine implicated in MDSC recruitment. Mechanistically, inactivation of neddylation pathway inhibits activity of Cullin-RING ligase 1, a typical neddylation substrate, and induces accumulation of phosphorylated IκBα and subsequent blockage of NF-κB translocation, thus suppressing transcriptional activation of mCxcl5 or hCXCL6. Collectively, our data suggest that neddylation-NF-κB-mCXCL5 axis is involved in MDSC recruitment to the tumor sites and demonstrate that neddylation pathway is a good therapeutic target for patients with LUAD, particularly those receiving anti-MDSC therapy.

NAE modulators: A potential therapy for gastric carcinoma.

Neural precursor cell expressed developmentally downregulated protein-8 (NEDD8) is a ubiquitin-like protein, which activates an important post-translational modification process: neddylation, thereby regulating the stability and degradation of various proteins related to multiple physiological processes. And the abnormal activation of NEDD8 (overexpression or underexpression) is related to the occurrence of multiple cancers including gastric carcinoma. NEDD8 activating enzyme (NAE), a key enzyme for the activation of NEDD8, controls the initiation of the NEDD8 transfer cascade, which is an important target for anti-tumor drugs. With the disclosure of the anti-tumor mechanism, NAE modulators (inhibitors and agonists) have gradually become a research hotspot in the development of anti-tumor drugs. And the application of NAE modulators has also been further expanded, not only limited to certain hematological tumors, its therapeutic potential in multiple solid tumors, especially gastric carcinoma, has been gradually uncovered. This paper mainly explains the structural characteristics, catalytic sites, and mechanism of NAE. And the relationships between neddylation and tumors are also elaborated from the perspective of NAE regulating the downstream pathways. In addition, the NAE modulators reported in recent years were reviewed, mainly focusing on their discovery processes, structure-activity relationships, inhibitory efficacy, pharmacological mechanism, and clinical research. And we reasonably predict the application of NAE modulators in gastric carcinoma, according to its relationship with neddylation. We summarize the issues in NAE modulator development and discuss the possible development directions.