S55746 (BLC201)

S55746 is an orally active, selective and potent BCL-2 inhibitor, with a Ki of 1.3 nM.

Signaling Pathways >> Apoptosis >> Bcl-2 Family

Research Areas >> Cancer

Bcl-2:1.3 nM (Ki)

Bcl-xL:520 nM (Ki)

Bcl-2:3.9 nM (Kd)

Bcl-xL:186 nM (Kd)

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].

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].

Mice[1] Experiments are performed in SCID/beige female mice. RS4;11 Acute Lymphoblastic Leukemia cell lines and human cell lines are used. For each experiment, female SCID/beige mice are implanted subcutaneously with 3×106 Toledo or RS4;11. Body weights are recorded and tumors are measured with digital calipers twice to three times a week. When tumors reached approximately 200 mm3 for efficacy studies or 300 mm3 for pharmacodynamics studies, mice are randomized. S55746 is formulated in PEG300/EtOH/water (40/10/50). Mice are treated via oral gavage at 10 mL/kg with different doses (e.g., S55746: 20, 50, 100 mg/kg)[1].

[1]. Casara P, et al. S55746 is a novel orally active BCL-2 selective and potent inhibitor that impairs hematological tumor growth. Oncotarget. 2018 Apr 13;9(28):20075-20088.

Venetoclax (ABT-199) | ABT-263 | S63845 | ABT-737 | Obatoclax Mesylate | A-1210477 | A-1155463 | WEHI-539 hydrochloride | A-1331852 | Bax inhibitor peptide V5 | FX 1 | Gambogic Acid | TW-37 | UMI-77 | Acetate gossypol