Glioblastoma (GBM) is among the most aggressive primary brain tumors, marked by rapid proliferation, therapeutic resistance, and profound intratumoral heterogeneity. Epigenetic regulators such as lysine-specific demethylase 1A (KDM1A) and histone deacetylase 2 (HDAC2) are aberrantly expressed in resistant GBM subpopulations and strongly correlate with poor clinical outcomes. Here, we assessed the therapeutic potential of MPT0G521, a dual KDM1A/class I HDAC inhibitor, in disrupting epigenetic regulation and cell cycle progression. Bioinformatic analyses of resistance-associated gene profiles (temozolomide and 2 Gy radiation) and single-cell transcriptomic datasets from distinct tumor regions revealed enrichment of KDM1A and HDAC2 in high-cycling GBM clusters, particularly at invasive margins prone to recurrence. Functional assays demonstrated that MPT0G521 potently inhibited proliferation of both parental and temozolomide-resistant GBM cells, inducing G2/M arrest and apoptosis. Transcriptomic profiling further identified significant downregulation of centrosome integrity genes (FSD1, KIFC1), spindle regulators (TUBB, STMN1, KIF2C, KIF15), kinetochore components (AURKB, CDCA8, SPAG5), and G2/M checkpoint mediators (CENPF, MYBL2, CCNF, MYT1, CDC25A), resulting in disrupted mitotic progression. Mechanistically, MPT0G521 increased histone H3 methylation and acetylation, validating its dual inhibitory activity against KDM1A and class I HDACs. Collectively, these findings indicate that MPT0G521 disrupts the G2/M activation and mitotic machinery, thereby suppressing proliferative and resistant GBM subpopulations. This dual epigenetic strategy holds strong promise for overcoming GBM heterogeneity and reducing recurrence.
An-Chih Wu, J. Chuang, Jr-Jiun Liu et al.· Biochemical Pharmacology· 0 citations
Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, yet their efficacy remains limited by tumor resistance, immune-related adverse events, and poor response in microsatellite stable colorectal cancer (CRC). To address these challenges, dual monoamine oxidase A (MAO-A) and heat shock protein 90 (HSP90) inhibitors, MPT1B098 and MPT1B099, were developed and evaluated for their therapeutic potential and immune-modulatory efficacy in CRC.
Human and murine CRC cell lines were treated with MPT1B098 and MPT1B099 to assess their effects in cytotoxicity, cell migration, apoptosis, cell cycle arrest, and cell-surface PD-L1 expression. Western blotting was performed to evaluate key apoptotic and EMT-related markers. In vivo therapeutic efficacy and safety were evaluated using CT26 and MC38 subcutaneous syngeneic tumor models in BALB/c and C57BL/6 mice treated with MPT1B098, MPT1B099, and/or anti-PD1 antibodies. Tumor infiltration of CD8
+
T cells and tissue histopathology were evaluated by immunohistochemistry and H&E staining.
In vitro, MPT1B098 and MPT1B099 exhibited potent cytotoxicity against human and murine CRC cell lines with sub-micromolar IC
50
values, effectively inhibiting cell growth and migration while inducing apoptosis. Both compounds decreased cell-surface PD-L1 expression and modulated key apoptotic and EMT markers on Western blot. In vivo, both compounds were well tolerated at 10 mg/kg and significantly suppressed tumor growth in microsatellite instable and stable models. Notably, anti-PD1 monotherapy was effective only in MSI models, whereas MPT1B098 and MPT1B099 showed efficacy in both MSI and MSS tumors, with combination therapy producing a modest synergistic effect. Immunohistochemistry revealed increased CD8
+
T cell infiltration following treatment, particularly with MPT1B099 in combination with anti-PD1 antibodies.
These findings highlight the dual anti-tumor and immune-modulatory properties of MPT1B098 and MPT1B099, mediated in part through PD-L1 downregulation and enhanced intratumoral T cell infiltration. Dual targeting of MAO-A and HSP90 represents a promising novel strategy to overcome immunotherapy resistance in MSS CRC and enhance the therapeutic efficacy of immune checkpoint blockade.
Hui-Ju Tseng, Yueh-Lin Wu, Yan-Ling Chen et al.· Frontiers in Pharmacology· 0 citations
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