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| Targets |
Myeloid cell leukemia 1 (MCL1)
S63845 targets Myeloid Cell Leukemia 1 (MCL1), an anti-apoptotic protein of the Bcl-2 family. MCL1 is frequently overexpressed in various cancers (including hematologic malignancies and solid tumors), promoting tumor survival and chemoresistance by sequestering pro-apoptotic effectors like BAX and BAK. The active S63845 inhibitor binds to the BH3-binding groove of MCL1, displacing these effectors and triggering apoptosis. The (S,R)-isomer is the inactive form. |
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| ln Vitro |
Avoidance of Apoptosis is critical for the development and sustained growth of tumours. The pro-survival protein myeloid cell leukemia 1 (MCL1) is overexpressed in many cancers, but the development of small molecules targeting this protein that are amenable for clinical testing has been challenging. Here we describe S63845, a small molecule that specifically binds with high affinity to the BH3-binding groove of MCL1. Our mechanistic studies demonstrate that S63845 potently kills MCL1-dependent Cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the Bax/BAK-dependent mitochondrial apoptotic pathway. In vivo, S63845 shows potent anti-tumour activity with an acceptable safety margin as a single agent in several cancers. Moreover, MCL1 inhibition, either alone or in combination with other anti-cancer drugs, proved effective against several solid cancer-derived cell lines. These results point towards MCL1 as a target for the treatment of a wide range of tumours.[1]
S63845 is a potent MCL1 inhibitor with a Kd of 0.19 nM for human MCL1. In vitro, S63845 potently kills MCL1-dependent cancer cells by activating the mitochondrial apoptotic pathway. In triple-negative breast cancer (TNBC) and HER2-amplified cell lines, S63845 displayed synergistic activity with docetaxel, trastuzumab, or lapatinib. The (S,R)-isomer is the inactive control, showing no cytotoxicity or target engagement. |
| ln Vivo |
In vivo, S63845 is tolerable and effective in diverse cancer models, including hematologic malignancies and solid tumors. In preclinical xenograft models (e.g., multiple myeloma, AML, and breast cancer PDX models), active S63845 induces apoptosis, leading to significant tumor growth inhibition or regression. The inactive (S,R)-isomer is used as a control in these experiments to demonstrate that the therapeutic effect is specifically mediated by MCL1 inhibition.
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| Enzyme Assay |
A non-cell biochemical assay, typically a fluorescence polarization (FP) or TR-FRET, is used. Recombinant human MCL1 protein is incubated with a fluorescently-labeled BH3 peptide (e.g., BID or NOXA) and varying concentrations of the test compound. The (S,R)-isomer is used as a control. Active S63845 disrupts the MCL1-peptide complex, decreasing FRET signal/FP, allowing calculation of the Kd (0.19 nM).
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| Cell Assay |
A cell viability assay is performed in MCL1-dependent cancer cell lines (e.g., H929 multiple myeloma or MOLM-13 AML). Cells are seeded in 96-well plates and treated with serial dilutions of the active S63845 or the inactive (S,R)-isomer for 48-72 hours. Cell viability is measured using the CellTiter-Glo luminescent assay. The inactive isomer should show no reduction in viability compared to vehicle control.
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| Animal Protocol |
For xenograft studies, female immunodeficient mice (e.g., SCID or NSG) are implanted with MCL1-dependent tumor cells. When tumors reach ~150-200 mm3, mice are randomized (n=8-10/group). Treatment groups receive the active S63845 (dosed IP or IV, e.g., 25 mg/kg, QD or QOD), the inactive (S,R)-S63845 as a control, or vehicle. Tumor volume is measured via calipers twice weekly for up to 4 weeks. At endpoint, tumors are analyzed for cleaved caspase-3.
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| ADME/Pharmacokinetics |
As a research control isomer, PK data is not required. The active S63845 is typically formulated in a vehicle containing a high percentage of PEG and DMSO (e.g., 5% DMSO/30% PEG300/5% Tween 80/60% saline) for intraperitoneal (IP) administration. The active compound has a moderate terminal half-life (t1/2) in rodents, supporting QD or QOD dosing, and distributes well into tumor tissues.
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| Toxicity/Toxicokinetics |
The (S,R)-inactive isomer is non-toxic at control concentrations. The active compound S63845 is generally well-tolerated at efficacious doses in mice, with no significant body weight loss or overt toxicity. Clinically, BH3-mimetics like MCL1 inhibitors can cause hematologic side effects (thrombocytopenia) as on-target, dose-limiting toxicities. No genotoxicity has been reported for this research tool.
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| References | |
| Additional Infomation |
S63845 is a landmark research-grade chemical tool for validating MCL1 as an anti-cancer target. Its discovery, published in the journal Nature (Kotschy et al., 2016), showed the BH3-mimetic to have potent antitumor activity in multiple cancer models. (S,R)-S63845 is the inactive isomer control. The active compound has been further developed into clinical candidates (e.g., MIK665/S-64315). This product is for research use only.
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| Molecular Formula |
C39H37CLF4N6O6S
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|---|---|
| Molecular Weight |
829.26
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| Exact Mass |
828.212
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| Elemental Analysis |
C, 56.49; H, 4.50; Cl, 4.27; F, 9.16; N, 10.13; O, 11.58; S, 3.87
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| Related CAS # |
S63845;1799633-27-4;(R,R)-S63845
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| Appearance |
White to off-white solid powder
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| LogP |
5.7
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| Synonyms |
(S,R)-S-63845
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.2059 mL | 6.0295 mL | 12.0589 mL | |
| 5 mM | 0.2412 mL | 1.2059 mL | 2.4118 mL | |
| 10 mM | 0.1206 mL | 0.6029 mL | 1.2059 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Products are for research use only; We do not sell to patients
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