| Size | Price | Stock | Qty |
|---|---|---|---|
| 100μg |
|
||
| 1mg | |||
| Other Sizes |
| Targets |
MCL1 15 pM (Ki)
Murizatoclax targets MCL‑1 (myeloid cell leukemia‑1), an anti‑apoptotic member of the BCL‑2 protein family. It competitively binds to the BH3‑binding groove of MCL‑1 with a Ki of 15 pM, thereby preventing MCL‑1 from sequestering pro‑apoptotic BCL‑2 family members (such as BIM, NOXA, and PUMA). This leads to the release of activated BAX/BAK, mitochondrial outer membrane permeabilization, and subsequent apoptosis induction. |
|---|---|
| ln Vitro |
AMG 397 significantly reduces the interaction between MCL1 and BIM in OPM2 cells and, in less than an hour, causes observable increases in Caspase-3/7 activity[2].
In vitro, Murizatoclax potently kills MCL‑1‑dependent cancer cell lines at picomolar to low nanomolar concentrations. It induces apoptosis in hematological malignancies such as multiple myeloma, acute myeloid leukemia (AML), and non‑Hodgkin's lymphoma. The compound demonstrates high selectivity for MCL‑1 over other BCL‑2 family members (BCL‑xL, BCL‑2, BFL‑1, MCL‑2). |
| ln Vivo |
In mice with OPM2 xenografts, murizatoclax (25–50 mg/kg; po once or twice weekly) significantly reduces tumors[2]. At doses of 10, 30, and 60 mg/kg, respectively, murizatoclax (10-60 mg/kg; po twice weekly) yields 47% MOLM-13 orthotopic tumor growth inhibition (TGI), 99% TGI, and 75% regression[2].
In preclinical animal models, oral administration of Murizatoclax demonstrates robust antitumor activity in xenograft mouse models of MCL‑1‑dependent human tumors, including MV‑4‑11 (AML) and H929 (multiple myeloma) models. Dose‑dependent tumor growth inhibition and regression have been observed, accompanied by biomarker evidence of MCL‑1 target engagement and apoptosis induction. |
| Enzyme Assay |
For non‑cellular binding, the MCL‑1 protein is purified and labeled with a fluorescent BH3 peptide tracer (e.g., BIM). Murizatoclax is serially diluted in assay buffer and mixed with MCL‑1 protein and tracer. After equilibrium, fluorescence polarization (FP) or time‑resolved fluorescence resonance energy transfer (TR‑FRET) is used to calculate binding affinities (Ki). Alternatively, surface plasmon resonance (SPR) with immobilized MCL‑1 can be employed.
|
| Cell Assay |
MCL‑1‑dependent cancer cell lines (e.g., NCI‑H929, MV‑4‑11, Molm‑13) are seeded in 96‑well plates and treated with Murizatoclax (0.001-10,000 nM) for 48-72 h. Cell viability is assessed by CellTiter‑Glo or MTT assays to determine IC50 values. Apoptosis is confirmed by Annexin V/PI flow cytometry and Western blotting for PARP cleavage and caspase‑3/7 activation. Selectivity is verified in MCL‑1‑independent cell lines.
|
| Animal Protocol |
Female NOD/SCID or NSG mice with subcutaneous MV‑4‑11 or H929 xenografts are dosed orally with Murizatoclax once daily (QD) or twice daily (BID) at 3-30 mg/kg for 14-28 days. Tumor volume is measured twice weekly with calipers. At study termination, tumors are excised and analyzed for MCL‑1 target engagement (by measuring free BH3 peptide availability), apoptosis markers (cleaved caspase‑3, TUNEL), and pharmacokinetic exposure levels.
|
| ADME/Pharmacokinetics |
Murizatoclax (AMG 397) exhibits favorable oral bioavailability and pharmacokinetic properties supportive of once‑daily or twice‑daily dosing. Key parameters (e.g., Cmax, Tmax, AUC, t½) were evaluated in preclinical species. Murizatoclax demonstrates moderate plasma clearance and a terminal half‑life compatible with oral administration in rodent and non‑rodent models. Detailed PK parameters are published in the preclinical development literature.
|
| Toxicity/Toxicokinetics |
Toxicological assessment of Murizatoclax has been conducted in support of early clinical development. As an MCL‑1 inhibitor, on‑target toxicities may include dose‑dependent thrombocytopenia and lymphopenia due to the critical role of MCL‑1 in platelet and lymphocyte survival. Liver enzyme elevations and gastrointestinal disturbances have also been observed in preclinical safety studies. No formal FDA approval has been granted.
|
| References | |
| Additional Infomation |
Murizatoclax is an inhibitor of differentiation proteins inducible myeloid leukemia cells (Myeloid Leukemia-1; Mcl-1; Bcl2-L-3) with potential pro-apoptotic and anti-tumor activities. After administration, the MCL-1 inhibitor AMG 397 targets and binds to Mcl-1, thereby preventing Mcl-1 from binding to and inactivating certain pro-apoptotic proteins. This promotes apoptosis in Mcl-1-overexpressing cells. Mcl-1 is an anti-apoptotic protein belonging to the B-cell lymphoma 2 (Bcl-2) protein family, highly expressed in cancer cells and promoting tumor cell survival.
Murizatoclax (AMG 397) is an investigational anticancer drug originally developed by Amgen. It has advanced into Phase I clinical trials for the treatment of relapsed or refractory hematological malignancies, including acute myeloid leukemia (AML), multiple myeloma (MM), and non‑Hodgkin's lymphoma (NHL) (ClinicalTrials.gov identifier: NCT03465540). As of the latest updates, the clinical development program may have been modified or discontinued; researchers should consult current trial registries. |
| Molecular Formula |
C42H57CLN4O5S
|
|---|---|
| Molecular Weight |
765.443789243698
|
| Exact Mass |
764.373
|
| CAS # |
2245848-05-7
|
| Related CAS # |
2245848-05-7;
|
| PubChem CID |
138669688
|
| Appearance |
White to off-white solid powder
|
| LogP |
7.3
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
8
|
| Rotatable Bond Count |
3
|
| Heavy Atom Count |
53
|
| Complexity |
1440
|
| Defined Atom Stereocenter Count |
7
|
| SMILES |
ClC1C=CC2=C(C=1)CCC[C@@]12COC2C=CC3C(NS([C@H](C)[C@@H](C)CC=C[C@](CN4CCN5CCCC[C@@H]5C4)([C@@H]4CC[C@H]4CN(C=2C=3)C1)OC)(=O)=O)=O |t:27|
|
| InChi Key |
BJTFTQIBRVBSBH-VCQPVEJUSA-N
|
| InChi Code |
InChI=1S/C42H57ClN4O5S/c1-29-8-6-18-42(51-3,27-45-20-21-46-19-5-4-10-35(46)25-45)37-14-11-33(37)24-47-26-41(17-7-9-31-22-34(43)13-15-36(31)41)28-52-39-16-12-32(23-38(39)47)40(48)44-53(49,50)30(29)2/h6,12-13,15-16,18,22-23,29-30,33,35,37H,4-5,7-11,14,17,19-21,24-28H2,1-3H3,(H,44,48)/b18-6+/t29-,30+,33-,35+,37+,41-,42-/m0/s1
|
| Chemical Name |
(3'R,4S,6'R,7'R,8'E,11'S,12'R)-7'-[[(9aR)-1,3,4,6,7,8,9,9a-octahydropyrido[1,2-a]pyrazin-2-yl]methyl]-7-chloro-7'-methoxy-11',12'-dimethyl-13',13'-dioxospiro[2,3-dihydro-1H-naphthalene-4,22'-20-oxa-13λ6-thia-1,14-diazatetracyclo[14.7.2.03,6.019,24]pentacosa-8,16(25),17,19(24)-tetraene]-15'-one
|
| HS Tariff Code |
2934.99.9001
|
| 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)
|
| Solubility (In Vitro) |
DMSO : 10 mg/mL (13.06 mM)
|
|---|---|
| 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 | 1.3064 mL | 6.5322 mL | 13.0644 mL | |
| 5 mM | 0.2613 mL | 1.3064 mL | 2.6129 mL | |
| 10 mM | 0.1306 mL | 0.6532 mL | 1.3064 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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