MM927 is a potent NVL inhibitor with an IC50 value of 0.053 μM. It disrupts the biosynthesis of the 60S ribosomal subunit within the nucleolus, induces halfmer polysome formation, causes cell cycle arrest at the G1/S and G2/M phases, and triggers apoptosis (apoptosis). Demonstrating antitumor activity in both MOLM-13 acute myeloid leukemia (AML) and HCT116 colorectal cancer (CRC) xenograft models, MM927 can be utilized for studying AML and CRC cancers.

MM927 inhibits HCT116 cells (IC50 = 53 nM) and MOLM-13 cells (IC50 = 92 nM) over 72 hours. At a concentration of 0.5 μM for 24 hours, MM927 induces half-mer polysomes and reduces the free 60S/80S ribosomal peaks in the polysome profile of HCT116 NVL WT cells. When applied at 3 μM for 6 hours, MM927 repositions newly synthesized eL36-SNAP to non-ribosomal fractions, causing depletion from 60S/80S/polysome components in HCT116 cells. A longer exposure of 24 hours at the same concentration leads to reduced cytoplasmic signals of eL36-SNAP (60S) and nucleolar retention in HCT116 NVL WT cells. MM927 at 0.5 μM for 24 to 48 hours results in cell cycle arrest at the G1/S and G2/M phases in HCT116 mock cells. In MOLM-13 cells, MM927 (3 μM, 2-3 days) induces apoptosis, indicated by an increase in cleaved caspase-3 and a higher proportion of Annexin V positive cells. Additionally, MM927 inhibits the activity of HCT116 NVL AID/AID cells expressing exogenous human NVL with an IC50 of 0.051 μM and inhibits the same cells expressing exogenous mouse NVL with an IC50 of 0.207 μM.

MM927, administered at a dose of 35 mg/kg via intraperitoneal injection twice daily, effectively reduces the growth of HCT116 NVL WT tumor xenografts and decreases tumor burden in NSG mice over a period of 21 days, but shows no effect on HCT116 NVL R403WCRISPR tumor xenografts. Administered under the same conditions for 14 days, MM927 also diminishes leukemia disease burden in NSG mice. Additionally, a 3-day treatment of MM927 enhances nuclear p53 staining in HCT116 NVL WT tumor xenografts and decreases Ki-67 positive cell staining in NSG mice.