| Description: |
S55746 is an orally active, selective and potent BCL-2 inhibitor, with a Ki of 1.3 nM. |
| In Vivo: |
Caspase-3 activity after S55746 treatment at 25 and 100 mg/kg is about 11 and 28 times higher than in vehicle-treated animals, respectively. Antitumor activity of S55746 is then evaluated in RS4;11 and Toledo models, two models that display different in vitro sensitivities towards S55746 (71.6 nM in RS4;11 vs 401 nM in Toledo). In RS4;11 bearing SCID mice, daily oral gavage treatment of S55746 for 7 consecutive days induce significant anti-tumor activity compared to untreated animals. Seventeen days after beginning of treatment at 25 mg/kg, 50 mg/kg and 100 mg/kg, tumor growth inhibition is 67.1, 16.3 and −93.8 T/C respectively, with complete regression observed in all animals treated at 100 mg/kg. Efficacy of S55746 is also assessed in Toledo bearing mice. After 21 days of treatment, S55746 induces a significant tumor growth inhibition either at 200 or 300 mg/kg (13% and 2% T/C, respectively; p<0.05). In this model, S55746 and ABT-199 show similar anti-tumor efficacy[1]. |
| In Vitro: |
S55746 is a potent inhibitor of BCL-2 (Ki=1.3 nM). S55746 potently induces RS4;11 cell killing after 72 h of treatment with an IC50 of 71.6 nM. Interestingly, S55746 exhibits a much weaker activity in H146 (IC50=1.7 μM), a BCL-XL-dependent cell line, which expresses a low level of BCL-2 and high level of BCL-XL whereas ABT-263, which targets BCL-2 and BCL-XL, induces equivalent cell killing in both RS4;11 and H146 (41.5 nM and 49.7 nM, respectively). S55746-induced apoptosis in RS4;11 is mediated in part by the BAX effector protein since PARP cleavage is markedly inhibited in BAX-deficient RS4;11 cells. S55746 is shown to strongly induce apoptosis in BCL-2-dependent FL5.12 cells with a minor effect in BCL-XL-dependent FL5.12 cells[1]. |
