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Pevonedistat

TAK-924

NAE inhibitor (neddylation inhibitor, NEDD8-activating enzyme inhibitor)

Evidence Score

30

preclinical
Mechanism of Action

First-in-class, mechanism-based inhibitor of the NEDD8-activating enzyme (NAE1/UBA3), which initiates the neddylation cascade by activating NEDD8 for transfer to E2 conjugating enzymes (UBE2M, UBE2F) and ultimately to cullins. Neddylation of cullins activates cullin-RING E3 ubiquitin ligases, the largest family of ubiquitin E3 ligases. In SDH-deficient tumor cells, an unbiased genome-wide CRISPR-Cas9 synthetic lethality screen identified UBE2F — the neddylation E2 enzyme for cullin-5 — as a selective vulnerability: UBE2F loss suppressed growth specifically in SDHB-deficient chromaffin cells (Al Khazal et al., iScience 2026, PMID: 42181244). Pevonedistat (MLN4924) inhibits NAE upstream of both UBE2F and UBE2M, blocking the entire cullin neddylation cascade. The mechanistic basis for SDH-selectivity likely involves proteotoxic stress: SDH-deficient cells operating under chronic metabolic stress (TCA truncation, ROS, HIF activation) may be disproportionately dependent on cullin-RING-ligase-mediated protein quality control. Pevonedistat has demonstrated acceptable safety in Phase 1/2 trials in hematologic malignancies (Breakthrough Therapy designation by FDA for AML); investigation in SDH-deficient solid tumors is in the preclinical stage.

Pathway Connections
Neddylation / Ubiquitin-Proteasome Axis

An unbiased genome-wide CRISPR-Cas9 synthetic lethality screen in SDHB-deficient chromaffin cells identified the neddylation pathway as selectively essential for SDH-deficient tumor survival. Neddylation — attachment of the ubiquitin-like modifier NEDD8 to cullin-RING E3 ligases by NAE1/UBA3 and specific E2 enzymes — controls ubiquitin-mediated proteolysis. Loss of UBE2F suppressed growth of SDHB-deficient cells specifically, while neddylation inhibitors (pevonedistat, HA-9104) preferentially blocked proliferation in the SDH-deficient context (PMID 42181244).

Upstream event:

SDH loss → metabolic and proteotoxic stress → upregulated dependency on cullin-RING ligase-mediated protein degradation via neddylation

Downstream effects:

Selective UBE2F dependency in SDHB-deficient cellsCullin-RING ligase inactivation upon NAE inhibitionProteotoxic stress accumulationSelective growth suppression in SDH-deficient tumor cells
Molecular Targets

UBE2F

Ubiquitin-conjugating enzyme E2 F (neddylation E2)

synthetic_lethal

NEDD8-specific E2 conjugating enzyme that cooperates with RBX2 to neddylate cullin-5-based RING E3 ligases. Identified in an unbiased CRISPR screen as a selective synthetic lethal dependency in SDHB-deficient chromaffin cells: loss of UBE2F suppressed growth specifically in SDH-deficient cells, while loss of its related enzyme UBE2M promoted growth. Upstream NAE1/UBA3 inhibitors (e.g., pevonedistat) block the entire neddylation cascade (PMID 42181244).

UniProt: Q969M7

Quick Facts
Not FDA Approved
ChEMBL IDCHEMBL3188428
Evidence

Evidence from PubMed, OpenTargets, and ChEMBL will appear here once external data integration is enabled.

Coming in Phase 3

For research exploration only — not medical advice. Consult your doctor before acting on any information.

AI Analysis

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