Sonrotoclax

BCL-2 promotes tumor cell survival by sequestering proapoptotic proteins BAX and BAK, blocking mitochondrial outer membrane permeabilization and caspase activation; overexpression in B-cell malignancies mediates chemotherapy resistance. Sonrotoclax binds directly to the BH3-binding groove of BCL-2, displacing sequestered proapoptotic proteins and enabling BAX/BAK-mediated apoptosis. Crystal structures at 1.80 Å resolution show that sonrotoclax binds shallowly at the entrance of the P2 pocket — forming π-π and sulfonyl-π interactions with F112 and M115 respectively — achieving a BCL-2 binding affinity of KD = 0.046 nM, 24-fold greater than venetoclax. This shallow P2 binding mode prevents the steric clash with E152 that underlies the ~180-fold reduction in venetoclax affinity at the BCL-2 G101V mutant, with sonrotoclax retaining KD = 0.24 nM at G101V versus 29 nM for venetoclax. Sonrotoclax also demonstrates greater selectivity over BCL-XL than venetoclax (2000-fold vs. 325-fold), attributable in part to a sulfonyl-π interaction with M115, which is absent in BCL-XL where leucine occupies the equivalent position.