Fig. 5: Surveying synthetic lethal engagement of PRMT5-MTA complexes in MTAP-knockout cells.

A, B BRET probe CBH-002 validation data in HCT116 wild-type cells with WDR77 co-expression. HCT116 wild-type cells expressing NLuc-PRMT5 and unlabeled WDR77 DNA were treated with an 11 pt 3-fold series of GSK3326595 and an 8 pt, 2-fold titration series of CBH-002 for 2 h before BRET was measured. Data are the mean ± SEM of 3 independent experiments (n = 3). Data was fit with 4-parameter regression curve (see “Methods”). Data is plotted as both an affinity curve (A) and compound matrix (B). Orange triangles represent the optimal BRET probe concentration. C Representative compound concentration curves for GSK3326595 and MRTX1719 in HCT116 MTAP wild-type and MTAP^-/- cells. HCT116 cells co-expressing NLuc-PRMT5 and untagged WDR77 DNA were treated with 11 pt, 3-fold titrations of compound and an 8 pt 2-fold series of CBH-002 for 2 h prior to BRET measurement. The curves at optimal probe concentration (30 nM) are shown (for full matrices, see Fig. 5B, S6D–F). Curves were normalized and fit with a 4-parameter regression model (see “Methods”). Data are the mean ± SEM of 3 independent experiments (n = 3). D Titration matrix of MTA and MRTX1719 in HCT116 MTAP wild-type cells. HCT116 MTAP wild-type cells were treated with 30 nM CBH-002, and a matrix of MTA and MRTX1719 for 2 h before BRET was measured. Data were normalized and fit with a 2-parameter regression model (see “Methods”). Data are the mean ± SEM of 3 independent experiments (n = 3). E EC₅₀ measurements from D replotted as a function of MTA concentration. Yellow shaded area indicates linear range of quantitation. Data are the mean ±95% CI. Source data are provided as a Source Data file.