S63845

Cell lines

Haematological cancer-derived cell lines, Myeloma cell lines, Human lymphomas and chronic myeloid leukaemia cell lines

Preparation method

This compound is soluble in DMSO. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reacting condition

1-10 μM, 48 h, 37°C

Applications

S63845 is a small molecule MCL1 inhibitor with Ki < 1.2 nM. S63845 is effective against haematological cancer-derived cell lines. S63845 potently killed MCL1-dependent H929 multiple myeloma cells. S63845 disrupted binding of BAK and BAX to MCL1 in HeLa cells. Treatment with S63845 increased MCL1 protein levels in the HCT-116 colon carcinoma cell line. In the tested myeloma cell lines, some were highly sensitive to S63845 (IC50< 0.1 μM), six lines were moderately sensitive (0.1 μM < IC50 < 1 μM) and two lines were insensitive (IC50 > 1 μM). In a panel of human lymphomas and chronic myeloid leukaemia 11 cell lines: five lines were highly sensitive to S63845 (IC50 < 0.1 μM), three were moderately sensitive (0.1 μM < IC50< 1 μM) and three were insensitive to S63845 (IC50 >1 μM). In a panel of eight AML cell lines: all lines were sensitive to S63845 (IC50 4–233 nM) [1].

Animal models

Human multiple myeloma (H929 and AMO1) xenografted mice

Dosage form

Intravenously injected (i.v.), 25 mg/kg

Application

Intravenously injected (i.v.) S63845 exerted dose-dependent anti-tumour activity in human multiple myeloma (H929 and AMO1) xenografts in immunocompromised mice, with maximal tumour growth inhibition (TGImax) of 114% in the AMO1 model and 103% in the H929 model. S63845 (25 mg/kg) induced complete regression in 7 out of 8 of the mice at 100 days after treatment in the AMO1 model. S63845 (i.v., 25 mg/kg, 5 days) cured 70% of immuno-competent C57BL/6 mice bearing Eμ-Myc mouse lymphomas, with no side-effects evident in normal tissues. S63845 (12.5 mg/kg) showed potent activity in the MV4-11 human AML xenograft model, with a TGImax of 86%. S63845 (25 mg/kg) resulted in completeremission in 6 out of 8 mice after 80 days.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

[1]. Kotschy A, Szlavik Z, Murray J, et al. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature. 2016 Oct 19;538(7626):477-482.