BM-1197, a highly potent and specific dual inhibitor of Bcl-2 and Bcl-xL, effectively targets these proteins with IC50 values of 3.5 nM and 5.2 nM for Bcl-2 and Bcl-xL, respectively. This compound demonstrates notable antitumor activity in both in vitro and in vivo settings.

BCL2:3.5 nM (IC50), BCL-XL:5.2 nM (IC50)

BM-1197 (2-2000 nM; 3 d) has marginal cytotoxicity against wild-type mouse embryonic fibroblast (MEF) cells but exerts potent growth-inhibitory activity in the MCL1 ?/? cells[1]. BM-1197 shows potent growth-inhibitory activities in 7 small cell lung cancer (SCLC) cell lines with IC 50 s <100 nM, moderate activity in 3 SCLC cell lines with IC 50 s of ～600 nM and weak activity in 2 SCLC cell lines with IC 50 s >2000 nM[1]. BM-1197 (100 nM; 16 h) potently induces apoptosis in H146 cells[1]. BM-1197 (100 nM; 2 h) disrupts the association between Bcl-xl and Puma or Bim in H146 cells[1]. BM-1197 (100 nM; 0.5-2 h) induces Bax translocation, and it (3-30 nM; 2 h) induces cytochrome c release in H146 cells[1]. Cell Proliferation Assay[1]Cell Line: MEF/ MCL1 ?/? cells Concentration: 2, 20, 200, 2000 nM Incubation Time: 3 days Result: Inhibited MCL1 ?/? cells proliferation. Apoptosis Analysis[1]Cell Line: H146 cells Concentration: 100 nM Incubation Time: 16 hours Result: Induced apoptosis in a strictly Bax/Bak-dependent manner. Western Blot Analysis[1]Cell Line: H146 cells Concentration: 100 nM Incubation Time: 2 hours Result: Attenuated the associations between Bcl-xL and BimEL or Puma.

BM-1197 (10 mg/kg; i.v. daily 5 days per week for 2 weeks) results in rapid and complete tumor regression in all 8 mice in H146 and H1963 tumor model[1]. BM-1197 (15 mg/kg; i.v.) causes thrombocytopenia in mice but the effect is reversible even at highly efficacious doses[1]. BM-1197 (10 mg/kg; i.v. qd) exerts a strong anti-tumor effect and is well tolerated in OCI-Ly8 xenograft models[2]. Animal Model: SCID mice bearing H146 cells[1]Dosage: 10 mg/kg Administration: I.v. daily 5 days per week for 2 weeks Result: Remained tumor free for at least 32 days after the end of the treatment.