NSD2-IN-6 is a selective inhibitor of NSD2, with an IC50 of 3.8 nM for NSD2 and 274 nM for NSD1. It reduces H3K36me2 levels and reverses cellular plasticity by restoring androgen receptor (AR) signaling pathways. In organoid models, NSD2-IN-6 prompts a transition of cell states from cluster 2 and cluster 3 to cluster 1. In vivo, it exhibits antitumor activity by reversing tumor cell plasticity, inhibiting growth, and promoting apoptosis. NSD2-IN-6 is useful for research in prostate cancer.

EZH1:3.8 nM

NSD2-IN-6 (compound NSD2i) significantly reduces H3K36me2 levels in NPPO-1NE organoids. Treatment with NSD2-IN-6 promotes a notable shift in cell state from clusters 2 and 3 to cluster 1, while enhancing the expression of classical androgen receptor target genes. In combination with Enzalutamide, NSD2-IN-6 has little or no effect on AR expression in non-neuroendocrine organoids. NSD2-IN-6 (1 µM, 17 days) increases sensitivity of NPPO-1NE, NPPO-2, NPPO-4, and NPPO-6 organoids to Enzalutamide, with EC50 values of 0.34, 2.7, 1.6, and 20 µM, respectively. When tested at 0.3-10 µM over 26 days, NSD2-IN-6 is ineffective on NSD2-knockout NPPO-1 and NPPO-2 organoids, showing only minor effects on NSD2-knockout MSKPCa10 organoids. NSD2-IN-6 (10 µM, 21 days) reduces H3K36me2 expression and slightly upregulates H3K27me3 in MSKPCa10, MSKPCa14, WCM154, WCM1262, and MSKPCa2 human CRPC organoid cell lines. In WCM1262, it results in loss of lineage marker CD56 and upregulation of AR, while in MSKPCa2, it causes a reduction in organoid size and positive immunostaining for cleaved caspase 3. NSD2-IN-6 (0.3-10 µM, 21 days) decreases cell viability post-Enzalutamide treatment in MSKPCa10, MSKPCa14, WCM154, WCM1262, and MSKPCa2 organoid cell lines, yielding high Bliss synergy scores and inducing apoptosis in a dose-dependent manner.

NSD2-IN-6 (compound NSD2i), administered orally at 75-300 mg/kg once daily for 5 days, reduces H3K36me2 levels in xenograft tumors of human-derived prostate cancer organoids in mice. Additionally, NSD2-IN-6 at 150 mg/kg, given orally once daily for 42 days, exhibits antitumor activity by reversing tumor cell plasticity, inhibiting growth, and promoting apoptosis in a mouse model of human-derived prostate cancer organoid xenografts.