Pevonedistat in Cancer Treatment: Mechanisms and Prospects

Pevonedistat is an investigational cancer therapy that targets the NEDD8-activating enzyme (NAE), disrupting protein degradation pathways essential for tumor cell survival. By interfering with this process, pevonedistat has shown promise in preclinical and clinical studies for various malignancies, particularly hematologic cancers and certain solid tumors.

Understanding its therapeutic potential requires examining its molecular mechanism, effects on cellular processes, and outcomes from ongoing research.

Role of Nedd8 in Protein Regulation

The NEDD8 (Neural Precursor Cell Expressed, Developmentally Downregulated 8) protein plays a crucial role in post-translational modification by activating cullin-RING ligases (CRLs), a major class of ubiquitin ligases responsible for targeted protein degradation. This process, known as neddylation, involves the conjugation of NEDD8 to cullin proteins, enhancing CRL activity and facilitating the ubiquitination of substrates that regulate cell cycle progression, DNA replication, and stress responses. Without proper neddylation, CRLs remain inactive, leading to the accumulation of proteins that would otherwise be degraded, disrupting cellular homeostasis and contributing to oncogenesis.

The neddylation cascade begins with the NEDD8-activating enzyme (NAE), a heterodimer composed of APPBP1 and UBA3, which catalyzes the ATP-dependent activation of NEDD8. Activated NEDD8 is transferred to the NEDD8-conjugating enzyme UBC12, which facilitates its attachment to cullin substrates with the assistance of NEDD8 E3 ligases. This modification induces a conformational change in CRLs, increasing their affinity for ubiquitin-conjugating enzymes and enabling the polyubiquitination of target proteins. Among the most well-characterized CRL substrates are p27, CDT1, and IκBα, which regulate cell cycle progression and genomic stability. Dysregulation of this pathway has been implicated in tumorigenesis, as excessive CRL activity can lead to tumor suppressor degradation, while insufficient neddylation results in the persistence of oncogenic factors.

Beyond CRL activation, NEDD8 influences ribosome biogenesis, DNA damage repair, and oxidative stress responses. Neddylation modulates ribosomal protein stability, ensuring proper assembly and function. Additionally, NEDD8 modification of proteins such as p53-binding protein 1 (53BP1) and Fanconi anemia complementation group D2 (FANCD2) is necessary for efficient DNA repair, highlighting its role in maintaining genomic integrity. Given that cancer cells exploit these pathways for rapid proliferation and apoptosis evasion, targeting NEDD8-dependent mechanisms has emerged as a promising therapeutic strategy.

Mechanism of Action

Pevonedistat selectively inhibits NEDD8-activating enzyme (NAE), blocking NEDD8 conjugation to cullin proteins and inactivating CRLs. This disruption prevents the degradation of key regulatory proteins, leading to the accumulation of factors that govern cell cycle progression, DNA replication, and stress responses. The resulting proteotoxic stress is particularly lethal to cancer cells, which rely on heightened proteasomal activity for survival.

A key consequence of CRL inhibition is CDT1 stabilization, a licensing factor essential for DNA replication. Normally, CDT1 is tightly regulated to prevent re-replication, which induces genomic instability and apoptosis. Pevonedistat-induced CDT1 accumulation triggers aberrant DNA synthesis, leading to replication stress characterized by stalled replication forks and DNA damage. Rapidly proliferating tumor cells, which depend on efficient DNA replication, are especially vulnerable to this effect.

Pevonedistat also enforces a G1-phase arrest by stabilizing p27, a cyclin-dependent kinase inhibitor that suppresses cell cycle progression. Preventing p27 degradation inhibits CDK2-mediated phosphorylation of retinoblastoma protein (Rb), halting the transition from G1 to S phase. Additionally, the accumulation of IκBα, an inhibitory regulator of NF-κB signaling, sensitizes tumor cells to apoptosis by dampening pro-survival transcriptional programs. The combination of these effects disrupts multiple oncogenic pathways, amplifying pevonedistat’s cytotoxic impact.

Pharmacologic Properties

Pevonedistat exhibits a well-defined pharmacokinetic and pharmacodynamic profile. Following administration, it covalently binds to NEDD8-activating enzyme (NAE), ensuring sustained neddylation inhibition. The drug reaches peak plasma concentrations within one to two hours post-infusion, with a biphasic elimination pattern—an initial rapid decline followed by a prolonged terminal half-life. Its pharmacokinetics are influenced by hepatic metabolism, renal clearance, and plasma protein binding.

Metabolism occurs primarily in the liver via cytochrome P450 enzymes, particularly CYP3A4, suggesting potential drug-drug interactions with CYP3A4 inhibitors or inducers commonly used in oncology. Agents such as ketoconazole or rifampin can alter pevonedistat plasma levels, requiring dose adjustments. Renal excretion plays a secondary role, with a fraction of the drug eliminated unchanged in urine, necessitating renal function monitoring in patients with impaired clearance.

The pharmacodynamic effects of pevonedistat correlate with CRL inhibition, leading to measurable intracellular protein changes. Dose-response studies indicate a saturation threshold, beyond which escalating doses do not yield proportional therapeutic benefit. Preclinical models and early-phase clinical trials have established optimal dosing schedules, typically on a five-day or three-day regimen within a 21-day cycle, balancing sustained target inhibition with manageable toxicity.

Effects on Cell Cycle

Pevonedistat disrupts cell cycle progression by stabilizing regulatory proteins that would otherwise be degraded. One of its most pronounced effects is CDT1 accumulation, a replication licensing factor essential for DNA synthesis. Normally, CDT1 levels are tightly controlled to prevent re-replication, which leads to excessive DNA synthesis and genomic instability. Pevonedistat-induced CDT1 accumulation forces cells into unscheduled replication, triggering replication stress and DNA damage, often culminating in apoptosis in rapidly dividing cancer cells.

Additionally, pevonedistat enforces a G1-phase arrest by stabilizing p27, a cyclin-dependent kinase inhibitor. Preventing p27 degradation suppresses CDK2-mediated phosphorylation of retinoblastoma protein (Rb), maintaining Rb in its hypophosphorylated state and blocking the G1-to-S phase transition. This blockade is particularly harmful to tumor cells reliant on unchecked proliferation. Furthermore, pevonedistat-induced accumulation of WEE1, a kinase that inhibits CDK1, reinforces a G2-phase delay, exacerbating cell cycle dysregulation and increasing susceptibility to mitotic catastrophe.

Investigations in Hematologic Tumors

Pevonedistat has shown promise in hematologic malignancies, particularly acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), where dysregulated protein homeostasis drives disease progression. By inhibiting NEDD8-activating enzyme (NAE), pevonedistat disrupts ubiquitin-mediated protein degradation, leading to the accumulation of tumor-suppressive factors that impede leukemic cell proliferation. AML cells are especially sensitive to pevonedistat due to their reliance on cullin-RING ligase (CRL) activity for maintaining oncogenic signaling.

Clinical trials have reinforced these findings, with Phase I and II studies evaluating pevonedistat in combination with azacitidine demonstrating encouraging efficacy and tolerability. In a multicenter Phase II trial, patients with high-risk MDS and AML receiving this combination exhibited improved overall response rates compared to those receiving azacitidine alone. The synergy is attributed to pevonedistat’s ability to induce replication stress and DNA damage, enhancing azacitidine’s cytotoxic effects. Furthermore, pevonedistat’s impact on NF-κB signaling increases apoptosis in leukemic cells, reducing their ability to evade programmed cell death. These promising results have prompted further studies to optimize dosing regimens and identify patient subgroups most likely to benefit from pevonedistat-based therapies.

Investigations in Solid Tumors

While pevonedistat’s impact has been most extensively studied in hematologic malignancies, its potential in solid tumors is gaining attention. Many solid tumors exhibit aberrant protein turnover due to dysregulated CRL activity, making them susceptible to NAE inhibition. Preclinical models have demonstrated pevonedistat’s anti-tumor effects in malignancies such as non-small cell lung cancer (NSCLC), melanoma, and pancreatic cancer by inducing replication stress and disrupting key survival pathways. In NSCLC xenografts, pevonedistat stabilizes proteins involved in cell cycle arrest and apoptosis, leading to DNA damage accumulation and tumor suppression.

Early-phase clinical trials have explored pevonedistat as a monotherapy and in combination with chemotherapy. In a Phase I trial involving patients with refractory solid tumors, pevonedistat achieved disease stabilization in a subset of participants, particularly those with highly proliferative tumors. Its combination with DNA-damaging agents is hypothesized to enhance efficacy by exacerbating replication stress, a vulnerability in aggressive cancers. Ongoing research aims to identify biomarkers predicting response to pevonedistat and explore combination strategies to maximize therapeutic impact while mitigating resistance.