| Description: |
S63845 is a potent and selective myeloid cell leukemia 1 (MCL1) inhibitor with a Kd of 0.19 nM for human MCL1. |
| Target: |
MCL1:0.19 nM (Kd) |
| In Vivo: |
S63845 shows potent anti-tumour activity with an acceptable safety margin as a single agent in several cancers. Intravenously injected (i.v.) S63845 exerts dose-dependent anti-tumour activity in human multiple myeloma (H929 and AMO1) xenografts in immunocompromised mice, with maximal tumour growth inhibition of 114% in the AMO1 model and 103% in the H929 model. At 25 mg/kg, S63845 induces complete regression in 7 out of 8 of the mice at 100 days after treatment in the AMO1 model[1]. |
| In Vitro: |
The pro-survival protein myeloid cell leukemia 1 (MCL1) is over expressed in many cancers. S63845 is a small molecule that specifically binds with high affinity to the BH3-binding groove of MCL1. S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the BAX/BAK-dependent mitochondrial apoptotic pathway. The activity of S63845 is next evaluated in a panel of eight AML cell lines: all lines are sensitive to S63845 (IC50=4-233 nM)[1]. |
| Kinase Assay: |
10 mM HEPES pH 7.4, 175 mM NaCl, 25 μM EDTA, 1 mM TCEP, 0.01% P20 and 1% DMSO is used as a running buffer. The ligand surface is generated using double His-tagged proteins. Serial dilutions of the compound in buffer are injected over the protein surface. All sample measurements are performed at a flow rate of 30 μL per min (injection time 120 s, dissociation time 360 s). The sensor surface is regenerated by consecutive injections of 0.35 M EDTA pH 8.0 with 0.1 mg/mL trypsin, 0.5 M imidazole and 45% DMSO (60 s, 15 μL per min)[1]. |
| Cell Assay: |
Cells are treated with increasing doses of S63845 (typically 0.008, 0.025, 0.04, 0.2, 1, 5 μM) for 24 h. Cells are stained with Annexin V-FITC and propidium iodide, analysed on a FACS Calibur and live cells are recorded. Data are presented as per cent cell death induction relative to cells cultured in medium alone[1]. |
| Animal Administration: |
Mice: S63845 is formulated extemporaneously in 25 mM HCl, 20% 2-hydroxy propyl β -cyclo dextrin 20% and administrated at the 6.25, 12.5, 25 mg/kg for 0, 20, 40, 60, 80 days. Tumour growth inhibition (TGImax) is calculated[1]. |
| References: |
[1]. Kotschy A, et al. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature. 2016 Oct 27;538(7626):477-482. |
