small-molecule inhibitors for prmt5  (Chembridge)

Journal: Neuro-Oncology

Article Title: PRMT5 as a druggable target for glioblastoma therapy

doi: 10.1093/neuonc/nox206

Figure Lengend Snippet: PRMT5 inhibitors affect the viability and tumor growth in vitro and in vivo. (A) Viability of GBMNS-30 treated with increasing doses of the indicated drugs; 72 h posttreatment, cells were subjected to MTT assay to measure the viability. (B) Kaplan–Meier survival curves of GBMNS-30 bearing fish treated with the indicated drugs (treated day 5 post-implantation) for 5 days. Animals were followed for survival post tumor implantation (n = 24/group); P-values were adjusted for multiple comparisons by Holm’s procedure (** and ## P ≤ 0.05). (C) Spinning disk confocal fluorescent imaging of relative tumor growth on day 5 (day of treatment initiation) and day 10 post tumor cell implantation in one representative fish from each group from the survival study in (B) (bar: 50 µm). MTT = 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide.

Article Snippet: Small-molecule inhibitors for PRMT5 were developed using the crystal structure of rat PRMT1 as a primary template for modeling a human in silico catalytic domain and utilizing the ChemBridge CNS-Set library of 10000 small molecules.

Techniques: In Vitro, In Vivo, MTT Assay, Tumor Implantation, Imaging

Journal: Neuro-Oncology

Article Title: PRMT5 as a druggable target for glioblastoma therapy

doi: 10.1093/neuonc/nox206

Figure Lengend Snippet: CMP5 mediated inhibition of PRMT5 catalytic activity in mice and tumor cell proliferation. (A) The brain tissue (0–6 h) and plasma (0–8 h) concentration-time profile of CMP5 for 3 formulations. (B) Western blot analysis of GBMNS-30 and GBMNS-X12 treated with DMSO (Ctrl) or CMP5 (25 µM) for 72 hours. Posttreatment cells were lysed and probed for methylated histone H4R3 and H3R8. Glyceraldehyde 3-phosphate dehydrogenase was used as the internal control. (C) Immunocytofluorescent imaging for H4R3 in GBMNS-30 cells after treatment with CMP5 for 72 hours (bar: 15 µm). (D) Relative growth of GBM30 cells grown as neurospheres (GBMNS) or differentiated cells (GBMDC) after treatment with increasing doses of CMP5 over time. A linear mixed model was used to account for the covariance structure due to repeat measures at different timepoints.

Article Snippet: Small-molecule inhibitors for PRMT5 were developed using the crystal structure of rat PRMT1 as a primary template for modeling a human in silico catalytic domain and utilizing the ChemBridge CNS-Set library of 10000 small molecules.

Techniques: Inhibition, Activity Assay, Clinical Proteomics, Concentration Assay, Western Blot, Methylation, Control, Imaging

Journal: Neuro-Oncology

Article Title: PRMT5 as a druggable target for glioblastoma therapy

doi: 10.1093/neuonc/nox206

Figure Lengend Snippet: CMP5 causes G1 cell cycle arrest in GBMNS. (A) Cell cycle analysis utilizing PI staining of indicated GBMNS and GBMDC treated with DMSO or CMP5 (25 µM) for 24 h posttreatment. Graph represents the percent of cell population in each stage of cell cycle (**P ≤ 0.001). (B) GBMNS-30 transfected with scrambled small interfering (si)RNA (Scr) or PRMT5 siRNA (P5i) were treated with DMSO or CMP5 (25 µM); 72 h posttreatment, cells were subjected to cell cycle analysis and the population of cells in each phase of the cell cycle were quantified. **Statistical significance of P5i + DMSO, Scr + CMP5, and P5i + CMP5 in comparison to control (Scr + DMSO) (**P ≤ 0.001). All the experiments were conducted in 3 biological triplicates.

Article Snippet: Small-molecule inhibitors for PRMT5 were developed using the crystal structure of rat PRMT1 as a primary template for modeling a human in silico catalytic domain and utilizing the ChemBridge CNS-Set library of 10000 small molecules.

Techniques: Cell Cycle Assay, Staining, Transfection, Comparison, Control