Fig. 5
ARV-825 redirects CRLCRBN to disrupt BET protein dependency of liposarcoma (LPS). a Heatmaps for the mean IC50 values of BET-targeting agents in LPS and osteosarcoma (U2OS, MG63) cell lines. IC50 values of ARV-825 in U2OS, MG63, and LiSa-2 cells exceeded the maximum dose (1 µM) and were set as 1 µM for heat map illustration. b Chemical structure of ARV-825. c, d Effects of ARV-825 and OTX015 treatments on c cell cycle progression and d cellular BrdU incorporation in LPS141 cells (200 nM, 24 h). e Dose-dependent inhibition of clonogenicity of LPS cells on soft agar by either ARV-825 or OTX015. f–h Effect of ARV-825 treatment on f animal body weight (n = 5), g xenograft volume (n = 10), and h weight of LPS141 xenografts at endpoint (n = 10). i, j Effect of ARV-825 treatment on weight of endpoint xenografts from i LP6 and j MLS402 (n = 8). k Effect of ARV-825 treatment on overall survival time of mice-bearing distant metastasis of LPS141 cells (n = 7). l Temporal effects of ARV-825 and OTX015 (200 nM) on indicated proteins in LPS141 cells. m Effect of MG132 on the ability of ARV-825 to deplete BET proteins. LPS141 cells were treated with MG132 (5 µM) and/or ARV-825 (200 nM) for 8 h before harvest. n Effects of CRBN, DDB1, and RBX1 silencing on the anti-proliferative efficacy of ARV-825 in LPS141 cells. o Ectopic CRBN expression in CRBN-silenced cells reversed insensitivity to ARV-825. Data of c–j, n, and o represent mean ± SEM; n = 3 in c–e, n, and o. One-way analysis of variance (ANOVA) was applied for c–e; Student’s t-test (two-tailed) was applied in g–j; log-rank test was applied in k. Source data are provided as a Source Data file
