Preferable safety profiles of FCN-683 were shown with no potential hERG inhibitory effect and less drug-drug interaction potential, as evidenced by no inhibitory effect (IC50 >50 μM) on CYP2C9 enzyme compared with VEN (IC50 1.05 μM). Together, FCN-683 is highly potent, selective and highly efficacious against a variety of clinically relevant VEN-resistance BCL-2 mutations in vitro and in vivo and exhibits favorable PK and safety profiles, highlighting its therapeutic potential to become an effective therapeutic approach for VEN-naïve or -resistant BCL-2-addicted B-cell malignancies.