pevonedistat (MLN4924)

P2, N=164, Active, not recruiting, Takeda | Trial completion date: Dec 2024 --> Mar 2025

Representative drugs selected for further investigation included docetaxel, methotrexate, panobinostat, idarubicin, camptothecin, and pevonedistat. In conclusion, we identified several highly effective agents with potent anti-tumor activity in chondrosarcoma cells, independent of IDH mutation status. These agents represent promising candidates for chondrosarcoma therapy and warrant further preclinical investigation and potential inclusion in clinical trials.

The neddylation reaction could be regulated by NEDD8, its precursors, substrates, E1 activating enzymes, E2 binding enzymes, E3 ligases, de-neddylases, and its inhibitors, such as MLN4924. NEDD8 is widely expressed in the whole cell structure of multiple tissues and species, and neddylation related factors are highly expressed in metabolism related adrenal glands, thyroid glands, parathyroid glands, skeletal muscles, myocardium, and adipose tissues, related to metabolic cardiovascular, cerebrovascular and liver diseases, adipogenic and osteogenic differentiation, as well as tumor glycolysis and glucose metabolism resulting from angiogenesis and endothelial disfunction, hepatotoxicity, adipogenesis, osteogenesis, Warburg effect, and insulin function. This review provides researchers with a new approach to explore metabolic diseases via searching and analyzing the histological, cytological, and subcellular localization of neddylation specific molecules in databases, and exploring specific mechanism neddylation mediating metabolic diseases by searching for neddylation related terms with the development of pre-clinical neddylation pharmacological inhibitors.

Overall, MLN4924 disrupted Neddylation pathway and stabilized TSC2, thereby inactivating the mTOR pathway. The study provided a theoretical basis for the clinical potential of MLN4924 in improving treatment outcomes for HNSCC patients, offering a novel strategy for addressing this challenging disease.

Viability analysis following treatment with pevonedistat and SZL-P1-41 in SCLC cell lines and human SCLC-organoid models indicates that RepID expression determines the sensitivity to CRL-targeting anti-cancer drugs. These findings suggest that RepID represents a novel biomarker for NET and SCLC, and insights from RepID research in these cancers could lead to innovative therapeutic strategies.

P2, N=164, Active, not recruiting, Takeda | Trial completion date: Sep 2024 --> Dec 2024

P2, N=36, Active, not recruiting, National Cancer Institute (NCI) | N=52 --> 36 | Trial completion date: Dec 2024 --> Oct 2025 | Trial primary completion date: Dec 2024 --> Nov 2023

P2, N=71, Completed, Vanderbilt-Ingram Cancer Center | Active, not recruiting --> Completed | Trial completion date: Oct 2024 --> Nov 2023

P3, N=454, Completed, Takeda | Active, not recruiting --> Completed

P1, N=30, Completed, Children's Oncology Group | Active, not recruiting --> Completed

P2, N=52, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2024 --> Dec 2024 | Trial primary completion date: Oct 2024 --> Dec 2024

In our study, we observed that MLN4924, an inhibitor of the NEDD8-activating E1 enzyme, effectively impedes the progression of VC...Furthermore, the CBL-b C373 peptide effectively mitigated the inactive form of the E3 ligase activity of CBL-b, ultimately preventing VC. These findings provide compelling evidence that the NEDD8-dependent activation of PARP-1 represents a novel mechanism underlying vascular calcification and suggests a promising new therapeutic target for VC.

P1, N=18, Active, not recruiting, City of Hope Medical Center | Trial completion date: Jun 2024 --> Dec 2024 | Trial primary completion date: Jun 2024 --> Dec 2024

However, in vitro and in vivo experiments demonstrate that inhibiting NAE1 with MLN4924 leads to increased resistance of NPC to radiation. Targeting NAE1 for NPC treatment may have dual effects, inhibiting NPC proliferation while also increasing radiation resistance.

P2, N=164, Active, not recruiting, Takeda | Trial completion date: Jun 2024 --> Sep 2024

P1, N=30, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Jul 2024 --> Jun 2025 | Trial primary completion date: Jul 2024 --> Jun 2025

Vulnerability to MLN4924, a NAE inhibitor, is associated with elevated S-phase populations, DNA re-replication, and DNA damage...Loss of WT PTEN is associated with non-sensitivity to 3 different compounds that inhibit NAE in GBM. A NAE inhibition response gene set largely consisting of DNA replication genes could segregate GBM cell lines most resistant to NAEi and may be the basis for future development of NAE inhibition signatures of vulnerability and clinical trial enrollment within a precision medicine paradigm.

P3, N=454, Active, not recruiting, Takeda | Trial completion date: Jun 2024 --> Sep 2024

Biologically, MLN4924 combination with SLC7A11 inhibitor Imidazole Ketone Erastin (IKE) enhanced suppression of tumor growth. In human breast tumor tissues, SLC7A11 levels were negatively or positively correlated with KCTD10 or USP18, respectively. Collectively, our study defines how SLC7A11 and ferroptosis is coordinately regulated by the CRL3KCTD10/E3-USP18/DUB axis, and provides a sound rationale of drug combination to enhance anticancer efficacy.

Neddylation is activated in PTX-insensitive TNBC. Specifically, autophagy gene transcriptional activation mediated by the UBC12/TRIM25/TFEB axis reduces TNBC sensitivity to PTX. Neddylation suppression combination with PTX treatment shows a synergistic anti-tumor effect.

P1, N=16, Terminated, Medical College of Wisconsin | Completed --> Terminated; Takeda P3001 study didn't meet primary endpoint of improvement in event-free survival. There is no regulatory path forward for pevonedistat.

This study underscores the regulatory function and potential mechanism of neddylation modification on the phenotype of KIRC, identifying PSMB10 as a key regulatory target with a significant role in influencing the prognosis of KIRC.

P1, N=16, Completed, Medical College of Wisconsin | Active, not recruiting --> Completed

CHIR-99021, MLN4924, and YK4-279 were identified as the potential drugs for treatment. Finally, upregulated EIOGs genes PPFIA4 and SCN3B were found in colon adenocarcinoma and PPFIA4 and SCN3B were proved to promote cell proliferation and migration in vitro. We demonstrated here that EIOGs promoting a malignancy phenotype was related with poor survival and prognosis in CRC, which might be served as novel therapeutic targets in CRC management.

Treatment with the neural precursor cell expressed developmentally downregulated protein 8-activating enzyme inhibitor pevonedistat resulted in increased hPRLrL and the death of breast cancer cells. Treatment of breast cancer cells with ERK1/2 inhibitor ulixertinib resulted in decreased colony-forming ability and less proliferation. These studies suggest that the hPRLrI I-tail contributed to breast oncogenesis and may be a promising target for the development of new breast cancer therapies.

P2, N=27, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2024 --> Mar 2025

Among these, the development of cardiomyopathy, characterized by cardiac remodeling and eventual heart failure, stands as a major concern following Dox chemotherapy.In our current investigation, we have showcased the efficacy of MLN4924 in mitigating doxorubicin-induced cardiotoxicity through direct inhibition of the NEDD8-activating enzyme, NAE.MLN4924 demonstrated the ability to stabilize mitochondrial function post-doxorubicin treatment, diminish cardiomyocyte apoptosis, alleviate oxidative stress-induced damage in the myocardium, enhance cardiac contractile function, mitigate cardiac fibrosis, and impede cardiac remodeling associated with heart failure. At the mechanistic level, MLN4924 intervened in the neddylation process by inhibiting the NEDD8 activating enzyme, NAE, within the murine cardiac tissue subsequent to doxorubicin treatment.This intervention resulted in the suppression of NEDD8 protein expression, reduction in neddylation activity, and consequential manifestation of cardioprotective effects.Collectively, our findings posit MLN4924 as a potential therapeutic avenue for mitigating doxorubicin-induced cardiotoxicity by attenuating heightened neddylation activity through NAE inhibition, thereby offering a viable and promising treatment modality for afflicted patients.

NEDD8-activating enzyme (NAE) inhibitors, represented by MLN4924, target the only activation enzyme in the neddylation pathway that has been identified as an attractive target for cancer therapy...Together, the enhanced transcription mediated by miR-17-92 cluster inhibition and reduced degradation promoted the increase in BIM levels, resulting in a synergistic effect. Collectively, these findings highlight the need for further clinical investigation into the combination of BETi and NAEi as a promising strategy for cancer therapy.

Collectively, Ube2f or Diras2 plays a tumor-promoting or tumor-suppressive role in the mouse KrasG12D PDAC model, respectively. The UBE2F-CRL5ASB11 axis could serve as a valid target for pancreatic cancer, whereas the levels of UBE2F or DIRAS2 may serve as prognostic biomarkers for PDAC patients.

The combination of azacitidine, venetoclax and pevonedistat is safe and shows encouraging preliminary activity in patients with relapsed/refractory AML. (NCT04172844).

The multi -gene risk scoring model based on apoptosis might predict radiotherapy benefits of LUAD patients and for those radioresistant patients classified by the model we also provided effective adjuvant chemicals, which would be used to guide clinical treatment.

Therefore, neddylation inhibition is an attractive strategy for ATL therapy. Our findings support the use of MLN4924 in ATL clinical trials.

Pro-inflammatory cytokines and iron parameters were longitudinally assessed, which revealed suppression of interleukin-6 and interferon-gamma in a dose-dependent manner across a subset of patients. These results suggest that combination therapy targeting both JAK2 and NFκB may hold clinical merit for MPN patients.

P1, N=30, Active, not recruiting, City of Hope Medical Center | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

P1/2; Completed --> Terminated; Sponsor terminated study agreement

P2, N=164, Active, not recruiting, Takeda | Trial completion date: Jan 2024 --> Jun 2024

MLN4924 is an inhibitor of NEDD8, and its combined use with platinum drugs and irinotecan, as well as cycle inhibitors and NEDD activating enzyme inhibitors screened by drug repurposing, has been found to exert promising antitumor effects. The present review summarizes the recent progress made in the understanding of the role of NEDD8 in the advancement of CRC, suggesting that NEDD8 is a promising anti‑CRC target.

Furthermore, upregulated miRNAs and lncRNA-targeted mRNAs showed an evident enrichment of proliferation, differentiation, and apoptosis pathways, while downregulated ncRNA-targeted mRNAs were implicated in stem cell maintenance. Finally, our results proved that stemness (KLF4 and FGFR2) and epithelial-mesenchymal transition (ZEB2, TWIST2, SNAI2, CDH2, and VIM) factors, which are highly expressed in PC9GR cells compared to gefitinib-sensitive PC9 cells, could be abrogated with the neddylation inhibitor MLN4924 mainly through activation of epithelial differentiation pathways, thus exerting a protective role in lung cancer cells and chemosensitivity against lung tumorigenic transformation.

P2, N=71, Active, not recruiting, Vanderbilt-Ingram Cancer Center | Trial completion date: Jan 2024 --> Oct 2024

P1, N=16, Active, not recruiting, Medical College of Wisconsin | N=24 --> 16 | Trial completion date: Dec 2025 --> Dec 2024

The antineoplastic drug MLN4924 is an L1 inhibitor that suppresses NEDD8-activating enzyme activity...Interference with the functions of certain neddylation-dependent Cullin-really interesting new gene E3 ligases disrupts L1 reverse transcription and transposition activity. Our findings provide insights into the regulation of L1 retrotransposition and the identification of therapeutic targets for L1 dysfunctions.

P1, N=12, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed