Sonrotoclax is effective against the venetoclax-resistant BCL2 G101V mutant. (A) Binding affinities of sonrotoclax (left panel) and venetoclax (right panel) to the BCL2 G101V mutant measured by SPR. The curves in different colors represent the serial concentrations of sonrotoclax (0.625-20 nM) and venetoclax (6.25-800 nM). K_D values are presented as the mean values ± SDs for 4 independent experiments. (B) The disruption of the cellular BCL2:BIM complex in BCL2 G101V KI RS4;11 cells by sonrotoclax and venetoclax were detected using the MSD assay. (C) Inhibition of the cell viability in the parental RS4;11 and G101V KI cells was evaluated by a CellTiter-Glo luminescence assay. IC₅₀ values are presented as the mean values ± SDs for 3 independent experiments, with representative curves shown in panels B and C. (D-E) Assessment of in vivo PD/PK and efficacy of sonrotoclax and venetoclax in RS4;11 G101V xenograft models. Mice were treated with sonrotoclax or venetoclax at the indicated doses. Single-dose treatment was used to evaluate PD, and daily dosing was used for the efficacy study; all treatments were administered by oral gavage. For evaluation of PD/PK, plasma and tumor tissues were collected at the specified time points to measure drug concentrations and tumor cleaved caspase-3 (Asp175) levels by ELISA. For the efficacy study, the tumor volume was measured twice weekly, and the TGI was calculated on day 18 after dosing. The data are presented as the mean values ± SEMs of 3 mice at each time point (D) and 8 mice in each group (E); ∗∗∗∗P < .0001. ELISA, enzyme linked immunosorbent assay; PD, pharmacodynamics; PK, pharmacokinetics.