Sonrotoclax (BGB-11417) is a potent, selective and second-generation BCL2 inhibitor with IC50 of 0.014 nM and SPR KD value of 0.046 nM, overcomes BCL2 G101V mutation-induced venetoclax resistance.
Sonrotoclax inhibits the BCL2-BAK interaction with IC50 of 0.014 nM, exhibiting a 14-fold increase in potency compared to venetoclax (Cat#PC-49764).
Sonrotoclax also demonstrates better selectivity than venetoclax for other Bcl-2 family members, particularly BCL-xL (2000-fold), which is related to platelet toxicity and dose-limiting thrombocytopenia.
Sonrotoclax exhibits superior potency compared to venetoclax in different hematological cancer cells and xenograft models.
Sonrotoclax exhibits IC50 of 7.7 nM for BCL2 G101V mutant, RS4;11 cells, venetoclax has IC50 of 170 nM.
Sonrotoclax (50 mg/kg) resulted in rapid tumor regression in in RS4;11 BCL2 G101V xenografts mice (TGI of 106%), but venetoclax (50 mg/kg) exhibited inadequate efficacy (TGI of 61%).
Sonrotoclax also potently inhibits other BCL2 variants, including R129L, A113G, D103Y and V156D mutants (KD values=0.04-2.1 nM).
Sonrotoclax (50 mg/kg) showed robust anti-tumor activity in the KMS-12-PE D103Y xenograft model.