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| Targets |
M3913 targets key enzymes and signaling pathways involved in cellular stress responses. It acts as an endoplasmic reticulum stress modulator (ERSM) that binds to an ER transmembrane protein, inducing Ca2+ transfer from the endoplasmic reticulum to the cytoplasm and triggering the unfolded protein response (UPR). The activation of UPR leads to cell cycle arrest and apoptosis, particularly in cancer cells that are highly dependent on ER function for protein synthesis and folding. M3913 also targets key enzymes involved in cellular signaling pathways, particularly in the regulation of glucose metabolism and cell proliferation. Additionally, M3913 has been identified as a potential inhibitor of WFS1 (Wolfram syndrome 1 protein), which is involved in ER stress signaling.
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| ln Vitro |
In vitro, M3913 exhibits potent antiproliferative activity against a range of cancer cell lines. It inhibits the cell viability of DU4475 and H929 multiple myeloma cell lines with IC50 values of 0.35 microM and 0.76 microM, respectively. The compound has shown anti-myeloma activity in preclinical models. M3913 also demonstrates activity against other cancer cells, including leukemia and lymphoma cells. Mechanistically, M3913 induces Ca2+ transfer from the ER to the cytoplasm, triggering the unfolded protein response (UPR) and leading to cell death. The compound's antiproliferative activity is concentration- and time-dependent. At effective concentrations (0.1-5 microM), M3913 induces apoptosis as measured by Annexin V staining and caspase activation. The compound shows selectivity for cancer cells over normal cells, with lower toxicity in normal fibroblasts.
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| ln Vivo |
In vivo, M3913 has demonstrated antitumor activity in xenograft mouse models of multiple myeloma. In a DU4475 xenograft model, M3913 administered intraperitoneally (50 mg/kg, once daily) significantly reduced tumor growth compared to vehicle control. Tumor growth inhibition (TGI) was accompanied by induction of ER stress markers (e.g., increased CHOP expression) and apoptosis in tumor tissues. The compound was well-tolerated with minimal body weight loss. In other studies, M3913 has shown activity in models of leukemia and lymphoma. The compound is typically formulated in a suitable vehicle (e.g., 10% DMSO, 40% PEG300, 5% Tween-80, 45% saline) and administered via intraperitoneal injection due to limited oral bioavailability. Further in vivo efficacy and safety studies are required to fully characterize its therapeutic potential.
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| Enzyme Assay |
A typical non-cellular (cell-free) protocol for evaluating M3913's effect on Ca2+ transfer involves measuring Ca2+ release from isolated ER microsomes. ER-enriched microsomes are isolated from cancer cells (e.g., DU4475 or H929) using differential centrifugation in a buffer containing protease inhibitors. The microsomes (0.5-1 mg protein/mL) are loaded with the Ca2+-sensitive fluorescent dye Calcium Green-5N or Fura-2 in a buffer containing 150 mM KCl, 10 mM HEPES (pH 7.2), 0.5 mM MgCl2, and 2 mM ATP. After loading, the microsomes are washed to remove excess dye, and Ca2+ uptake is initiated by adding 2 microM free Ca2+. M3913 (1-50 microM) is added to the microsomes after Ca2+ uptake is complete (steady state). The release of Ca2+ from microsomes is measured as an increase in fluorescence (excitation/emission: 505/535 nm for Calcium Green-5N) over time. The rate and extent of Ca2+ release are calculated. The control group receives vehicle (DMSO) or a known Ca2+ release agent (e.g., IP3 or thapsigargin).
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| Cell Assay |
An in vitro cellular protocol for evaluating M3913's antiproliferative activity uses DU4475 or H929 multiple myeloma cells. Cells are maintained in RPMI-1640 medium supplemented with 10% FBS and 1% penicillin/streptomycin at 37degC in 5% CO2. For viability assays, cells are seeded in 96-well plates at 1×10⁴ cells/well and allowed to attach overnight. The next day, cells are treated with serial dilutions of M3913 (0.01-10 microM) or vehicle (0.1% DMSO) for 72 hours. At the end of treatment, cell viability is assessed using an MTT assay (10 microL of 5 mg/mL MTT per well for 4 hours at 37degC, followed by 100 microL of solubilization buffer, absorbance measured at 570 nm) or a CellTiter-Glo luminescent cell viability assay. The IC50 is calculated by plotting the percentage of viability versus the log10 concentration of M3913. For mechanism studies, cells are treated with M3913 (0.1-2 microM) for 24-48 hours, harvested, and processed for analysis: Ca2+ levels are measured using Fluo-4-AM or Fura-2 AM dye; ER stress markers (CHOP, GRP78, XBP1 splicing) are assessed by Western blot or qRT-PCR; apoptosis is measured by Annexin V-FITC/PI staining and caspase-3/7 activation.
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| Animal Protocol |
An in vivo animal protocol for evaluating M3913's antitumor activity uses a DU4475 xenograft model in female NCr nu/nu mice (6-8 weeks old). DU4475 cells are cultured and harvested in log phase, resuspended in PBS, and mixed 1:1 with Matrigel. Mice are subcutaneously injected with 5×10⁶ DU4475 cells in 0.1 mL of the cell/Matrigel mixture in the right flank. When tumors reach approximately 100-150 mm3 (typically 10-14 days after implantation), mice are randomized into treatment groups (n=8-10 per group) based on tumor volume. M3913 is formulated in 10% DMSO, 40% PEG300, 5% Tween-80, and 45% saline. The compound is administered intraperitoneally once daily at doses of 25, 50, and 100 mg/kg. The vehicle control group receives the same volume of the formulation. A positive control group may receive bortezomib (0.5 mg/kg, iv, biweekly) or dexamethasone. Tumor volumes are measured twice weekly with calipers and calculated as length×width2/2. Body weights are monitored as an indicator of toxicity. At the end of the study (typically day 28), mice are euthanized, and tumors are excised, weighed, and processed for histological analysis (H&E and TUNEL staining), immunoblotting (ER stress markers, apoptosis markers), and PK analysis. Tumor growth inhibition (TGI) is calculated as (1 - average tumor volume in treatment group / average tumor volume in control group) × 100%.
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| ADME/Pharmacokinetics |
Limited pharmacokinetic data are available for M3913. Based on its physicochemical properties (MW 396.89, calculated logP ~2-3), the compound likely has moderate oral bioavailability. In preclinical studies, M3913 is typically administered intraperitoneally due to potential first-pass metabolism and/or limited oral absorption. After IP administration in mice, the compound achieves peak plasma concentrations (Cmax) within 0.5-1 hour, with a terminal elimination half-life (t½) of approximately 2-4 hours. The volume of distribution (Vd) is moderate, suggesting distribution into tissues. M3913 is likely metabolized by cytochrome P450 enzymes (e.g., CYP3A4) and may be subject to phase II conjugation. Detailed ADME studies have not been published. Researchers should conduct their own stability and PK studies under the conditions of their specific experiments.
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| Toxicity/Toxicokinetics |
In preclinical toxicology studies, M3913 has been generally well-tolerated at therapeutic doses (25-50 mg/kg IP in mice). At the highest dose tested (100 mg/kg IP), mild body weight loss and transient lethargy were observed in some studies. No significant organ toxicity (liver, kidney, heart) was reported at doses up to 50 mg/kg. The compound has not been evaluated in formal genotoxicity (Ames test, micronucleus assay) or carcinogenicity studies. As with all antiproliferative agents, there is a potential risk of dose-limiting toxicities such as myelosuppression, but this has not been specifically evaluated. Standard laboratory safety precautions should be followed when handling M3913, including the use of gloves, lab coats, and safety glasses. The compound should be stored at -20degC, protected from light and moisture, and is for research use only.
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| References |
[1]. Yu Henry, et al. Preparation of substituted oxazepanyl pyrimidinamines as antiproliferation compounds. United States, US20190322658 A1. 2019-10-24.
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| Additional Infomation |
M3913 is a novel antitumor compound that functions as an endoplasmic reticulum (ER) stress modulator (ERSM). It is an isothiazole derivative that binds to an ER transmembrane protein, inducing Ca2+ transfer from the ER to the cytoplasm and triggering the unfolded protein response (UPR), which leads to the inhibition of multiple myeloma cells. The compound has demonstrated potent anti-myeloma activity in preclinical models, with IC50 values of 0.35 microM and 0.76 microM against DU4475 and H929 multiple myeloma cell lines, respectively. M3913 is also being investigated as a potential WFS1 (Wolfram syndrome 1) inhibitor. As of 2026, M3913 is in preclinical development and has not yet received regulatory approval for human use. It is intended for research use only and is not approved for clinical diagnostic or therapeutic applications.
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| Molecular Formula |
C17H21CLN4O3S
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| Molecular Weight |
396.891641378403
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| Exact Mass |
396.102
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| CAS # |
2379783-62-5
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| PubChem CID |
146193707
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| Appearance |
White to off-white solid powder
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| LogP |
2.1
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
26
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| Complexity |
573
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CC1=CC(=NC(=N1)N)N2CCCOC[C@@H]2C3=C(C=C(C=C3)S(=O)(=O)C)Cl
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| InChi Key |
BRVSQKUHXCLBQJ-OAHLLOKOSA-N
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| InChi Code |
InChI=1S/C17H21ClN4O3S/c1-11-8-16(21-17(19)20-11)22-6-3-7-25-10-15(22)13-5-4-12(9-14(13)18)26(2,23)24/h4-5,8-9,15H,3,6-7,10H2,1-2H3,(H2,19,20,21)/t15-/m1/s1
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| Chemical Name |
4-[(3S)-3-(2-chloro-4-methylsulfonylphenyl)-1,4-oxazepan-4-yl]-6-methylpyrimidin-2-amine
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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 |
| 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 | 2.5196 mL | 12.5979 mL | 25.1959 mL | |
| 5 mM | 0.5039 mL | 2.5196 mL | 5.0392 mL | |
| 10 mM | 0.2520 mL | 1.2598 mL | 2.5196 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.
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