pevonedistat (MLN4924)

Molecular docking further predicted that Glu63 of SOCS3 serves as a key residue for MLN4924 binding. Together, low-dose MLN4924 enhances SH-SY5Y cell viability and migration by targeting SOCS3 signaling, independent of JAK2/STAT3 signaling.

NLRP3 neddylation hinders its interaction with Trim31 and thereby inhibits its K48-linked ubiquitination and subsequent degradation. MLN4924, a potent compound NAE inhibitor in phase 1/2/3 clinical trials for cancers, alleviates psychological stress-induced NLRP3 inflammasome activation, microglia inflammatory activation, and anxiety-like behavior, suggesting novel clinical activity of MLN4924.

In conclusion, these findings suggest that MLN4924 exerts an anti-tumor effect on AML by inducing apoptosis through the ROS-EGR1-BTG2 signaling axis. Our research provides a novel theoretical basis for the clinical potential of MLN4924 in improving the treatment of AML patients, offers novel strategies for AML treatment, and thereby advances the implementation of precision medicine.

P1/2, N=53, Active, not recruiting, University of Southern California | Trial primary completion date: Oct 2026 --> Jun 2026

P1, N=18, Active, not recruiting, City of Hope Medical Center | Trial completion date: Nov 2025 --> Nov 2026 | Trial primary completion date: Nov 2025 --> Nov 2026

Mechanistically, TPM3-TRKA degradation by compound 9 was dependent on CRBN-mediated polyubiquitination and proteasomal degradation; accordingly, it was hindered by inhibitors of the proteasome (MG132) or Cullins (MLN4924), by dominant negative Cullin 4A mutant, and by free pomalidomide. Finally, a compound 9 derivative, compound 20, induced in vivo degradation of TMP3-TRKA in KM12 cells mouse xenografts. In conclusion, our study indicated that PROTAC-mediated degradation is an efficient strategy to intercept RET and TRKA oncogenic signaling.

P2, N=40, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Oct 2025 --> Oct 2026

P1/2, N=53, Active, not recruiting, University of Southern California | Trial primary completion date: Oct 2025 --> Oct 2026

Collectively, our results suggest that the neddylation pathway is deregulated in FP-RMS, representing a potential therapeutic target. Therefore, MLN4924 could be considered as an anti-tumorigenic compound and a novel radiosensitizer in FP-RMS.

Aside from allogeneic transplantation, the current standard of care approach for higher-risk myelodysplastic syndromes/neoplasms (HR-MDS) remains monotherapy with a hypomethylating agent (HMA) including azacitidine, decitabine, or oral decitabine/cedazuridine...In this review, we discuss lessons learned from the recently reported negative trials of azacitidine in combination with eprenetapopt (APR-246), magrolimab, pevonedistat, sabatolimab, tamibarotene, and venetoclax...Instead, we advocate for using the IWG 2023 response criteria to better capture clinically meaningful benefits in HR-MDS. Lastly, we emphasize the need for the scientific community to access patient-level data and samples from failed phase 3 trials in an efficient and expedited fashion to inform the development of subsequent trials.

Rescue experiments revealed TRIM58 knockdown attenuated MLN4924's suppression of AKT phosphorylation and associated pro-apoptotic effects. In this study, we show that MLN4924 can upregulate LINC01128, which binds to and segregates DNMT1, thereby inhibiting methylation modification of the TRIM58 and ultimately suppressing AML.

P2, N=164, Completed, Takeda | Active, not recruiting --> Completed