Sonrotoclax remains effective against other BCL2 mutants. (A) SPR measurements of the binding affinities of sonrotoclax and venetoclax to different BCL2 variants. The curves in different colors represent different concentrations of sonrotoclax (0.156-20 nM for D103Y, 0.313-20 nM for V156D, 0.078-20 nM for A113G, and 1.25-20 nM for R129L) and venetoclax (0.781-200 nM for D103Y, 1.56-100 nM for V156D, 0.781-400 nM for A113G, and 0.781-200 nM for R129L). K_D values are presented as the mean values ± SDs for 4 independent experiments. (B) Mutations are indicated on the BCL2 protein surface (gray). The mutated residues are highlighted in cyan. Sonrotoclax is represented by the yellow stick. (C) Superimposition of the structures of WT BCL2 (yellow) and the D103Y mutant (pale green) in complex with sonrotoclax. (D) Zoomed in view of D103 or Y103 involved in the binding of sonrotoclax or venetoclax. The hydrogen bonds are indicated by the cyan and yellow dashed lines. (E) Inhibition of the viability of parental and BCL2 D103Y KI KMS-12-PE cells was estimated by the CellTiter-Glo luminescence assay. IC₅₀ values are presented as the mean values ± SDs for 3 independent experiments, with representative curves shown in the figure. (F) Efficacy evaluation of sonrotoclax and venetoclax in the KMS-12-PE D103Y xenograft model. The tumor volumes are presented as the mean values ± SEMs of 8 animals in each group; ∗∗P < .01.