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.

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

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

Consequently, global neddylation inhibitor MLN4924 (Pevonedistat) and UBE2F-CRL5 axis inhibitor HA-9104 were shown to downregulate neddylation, suppressing UBE2F activity and selectively inhibiting growth of Sdhb -deficient imCCs. This unexpected result highlights the neddylation pathway as a promising druggable vulnerability in this cell culture model of SDH-deficient PPGL.

P2, N=164, Active, not recruiting, Takeda | Trial completion date: Jun 2025 --> Sep 2025

Biologically, MLN4924 effectively suppresses the migration and invasion of breast cancer cells in vitro and metastasis in vivo, which is largely rescued by ITGB4 overexpression. Taken together, our study revealed a new mechanism by which MLN4924 suppresses the migration and invasion of breast cancer cells by epigenetically inhibiting ITGB4 expression via enhancing H3K18 lactylation.

In vivo, RK-33 treatment in a xenograft BL model reduced tumor progression in all cell lines, albeit with variable efficacy compared to the clinical drug Pevonedistat, and again with the Daudi cells being the most responsive to the treatment...We therefore tested the inhibition of the glutathione pathway with buthionine sulfoximine and showed that it reduced the CC50 of RK-33 in BL cells lines. Our findings not only support DDX3X as a therapeutic target in BL but also provide evidence for a combinatorial treatment strategy to improve the efficacy of current treatments.