MI-503

Furthermore, we explored a novel combination therapy involving the histone methyltransferase inhibitor MI-503 and enzalutamide in AR-positive and AR splice variant-positive cell lines. Our results confirmed the synergistic therapeutic effects of this combination, which can continue to inhibit the AR signaling pathway during the CRPC stage, thereby delaying disease progression. Taken together, our findings elucidate a critical KMT2D/G3BP1/SPOP/AR regulatory axis in prostate cancer progression and propose that targeted inhibition of histone methylation in combination with anti-androgen therapy represents a promising strategy for the management of advanced prostate cancer.

Finally, the small-molecule inhibitor MI-503 combined with anti-PD-1 therapy suppressed tumor growth on the PDUTF platform. Collectively, KMT2D deficiency sensitizes tumor cells to ICB, and inhibiting KMT2D may represent a promising approach in combination with ICB to improve patient prognosis.

In a study with 143B cell-derived xenograft model, we found that MI-503 profoundly inhibited OS tumor growth in mice. Immunohistochemistry (IHC) study showed that MI-503 suppressed the H3K4 methylation and inhibited the expression of the cell proliferation biomarker Ki67 in 143B OS xenograft tissue.Overall, our findings demonstrated the potent anti-OS activity of MI-503 in both in vitro and in vivo models, which also indicated that Menin inhibitor may be a prospective therapeutic strategy for human OS.

Differential gene expression analysis by RNA-seq following combined pharmacological inhibition of SD70 and MI-503 revealed changes in numerous genes, with MYC target genes being the most significantly downregulated. Taken together, these data provide preclinical evidence that the combination of SD70 and MI-503 is a potential dual-targeted therapy for MLL::AF9 AML.

KMT2Ar-AML has been demonstrated to be sensitive to BCL2 inhibitor venetoclax (VEN), but these patients are unable to benefit from current VEN-based regimen (VEN plus azacitidine or low dose-cytarabine), so a novel and KMT2A rearrangement-specific targeting partner is required, and MENIN inhibitor (MEN1i) is a promising one. Hypoxia induction sensitized KMT2Ar-AML to VEN plus MI-503-mediated proliferation inhibition and apoptosis induction. Therefore, repressing HIF-1A-induced HDAC9 contributed to the synergistic effect of VEN and MEN1i in KMT2Ar-AML.

IGF2BP3 knockdown had a greater effect on increasing survival and attenuating disease than pharmacologic menin-MLL inhibition with MI-503 alone and showed enhanced anti-leukemic effects in combination. Our work shows that IGF2BP3 is an oncogenic amplifier of MLL-AF4 mediated leukemogenesis and is a potent therapeutic target and provides a paradigm for targeting leukemia at both the transcriptional and post-transcriptional level.

Moreover, MI503 inhibited FA-induced phosphorylation of epidermal growth factor receptor (EGFR), signal transducer and activator of transcription 3 and extracellular signal-regulated kinase-1/2 in injured kidneys. Collectively, these data suggest that MLL1 contributes to renal protection and functional recovery and promotes renal regeneration through a mechanism associated with activation of the EGFR signaling pathway.

We report that these mutations and variant promote tumor cell growth and gastrin expression by rendering menin protein unstable and prone to increased degradation. We demonstrate that the menin-MLL (mixed lineage leukemia) inhibitor MI-503 restores menin protein expression and function in vitro and in vivo, suggesting a potential novel therapeutic approach to target MEN1 GEP-NETs.

Finally, MI-503 was effective in abrogating serum or TGFβ1-induced transformation of renal interstitial fibroblasts to myofibroblasts in vitro. Taken together, these results suggest that targeting disruption of the MLL1-menin interaction attenuates renal fibrosis through inhibition of partial EMT and renal fibroblast activation.