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| Targets |
The primary target of Mcl1-IN-14 is Mcl-1, an anti-apoptotic protein that is often overexpressed in cancer cells. It acts as a PROTAC, binding to Mcl-1 and the E3 ligase cereblon (CRBN) simultaneously, leading to the ubiquitination and degradation of Mcl-1. It also inhibits Bcl-2.
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| ln Vitro |
By binding the E3 ligase cereblon (CRBN)-binding ligandpomalidomide to Mcl-1 Ross 1-6 with μM range affinities, PROTAC Mcl1 degrader-1 (Compound C3) induces ubiquitination and phosphosomal degradation of Mcl-1. In HeLa cells, PROTAC Mcl1 degrader-1 (0-10 μM; 0-24 hours) induces indirect depletion of Mcl-1 or Bcl-2 protein in a time-concentrated and dependent manner [1].
In vitro, Mcl1-IN-14 is a potent inhibitor of Mcl-1 with an IC50 of 0.78 μM. It induces time- and concentration-dependent depletion of Mcl-1 and Bcl-2 proteins in HeLa cells. It induces Mcl-1 depletion and PARP cleavage in H23 cells, indicating apoptosis. It shows cytotoxicity to H23 cells. |
| ln Vivo |
In vivo efficacy data for Mcl1-IN-14 are not extensively detailed. As a PROTAC, its activity is expected to translate to in vivo models, but specific studies have not been widely reported. Its ability to degrade Mcl-1 and induce apoptosis suggests potential for treating Mcl-1-dependent cancers.
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| Enzyme Assay |
For Mcl-1 degradation assays, cells are treated with Mcl1-IN-14, and Mcl-1 protein levels are analyzed by Western blot. The DC50 is determined. For apoptosis assays, cells are stained with Annexin V/PI and analyzed by flow cytometry. Caspase-3/7 activity is measured. For cell viability assays, MTT or CellTiter-Glo assays are used.
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| Cell Assay |
Western Blot Analysis[1]
Cell Types: HeLa cells and H23 cells Tested Concentrations: 0.3, 1.0, 3.0 and 10 μM Incubation Duration: 0 1 (0-2 μM; 24 hrs (hours)) Shows cytotoxicity to H23 cells[1]. -24 hour Experimental Results: Induces time- and concentration-dependent selective depletion of Mcl-1 or Bcl-2 protein in HeLa cells. Induces Mcl-1 depletion and PARP cleavage in H23 cells (0-10 μM; 12 hrs (hours)). For cellular studies, cancer cells (e.g., HeLa, H23) are cultured in appropriate medium. Mcl1-IN-14 is dissolved in DMSO and diluted in culture medium. Cells are treated with the compound. Protein levels (Mcl-1, Bcl-2, PARP) are analyzed by Western blot. Cell viability and apoptosis are assessed as described above. |
| Animal Protocol |
For in vivo efficacy studies, immunodeficient mice are implanted with Mcl-1-dependent cancer cells. Mcl1-IN-14 is formulated in vehicle and administered intraperitoneally or intravenously. Tumor growth is monitored. At study termination, tumors are excised and processed for Western blot analysis to confirm Mcl-1 degradation and apoptosis.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of Mcl1-IN-14 are not extensively reported. As a large PROTAC molecule (MW 909.84), it is expected to have poor oral bioavailability and would likely require parenteral administration. Its pharmacokinetic profile would need to be characterized for any therapeutic development.
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| Toxicity/Toxicokinetics |
Toxicological data for Mcl1-IN-14 are limited. No acute toxicity, organ-specific toxicity, or mutagenicity data have been reported. As with all research compounds, appropriate safety precautions should be taken during handling.
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| References | |
| Additional Infomation |
Mcl1-IN-14 (CAS 2163793-38-0) is a PROTAC that degrades Mcl-1 with an IC50 of 0.78 μM. It also inhibits Bcl-2. It has the molecular formula C₄₅H₄₅BrN₆O₈S and a molecular weight of 909.84. It induces apoptosis and is strictly for research use.
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| Molecular Formula |
C45H45BRN6O8S
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|---|---|
| Molecular Weight |
909.843209028244
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| Exact Mass |
908.22
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| CAS # |
2163793-38-0
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| PubChem CID |
139035048
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
6
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
19
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| Heavy Atom Count |
61
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| Complexity |
1660
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| Defined Atom Stereocenter Count |
0
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| SMILES |
BrC1C=CC(=CC=1)SC1C=CC2C(N(C(C3=CC=CC=1C=23)=O)CCNC(CCCCC(NCCCCCCNC1=CC=CC2C(N(C(C=21)=O)C1C(NC(CC1)=O)=O)=O)=O)=O)=O
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| InChi Key |
BORXNUWYWZOREQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C45H45BrN6O8S/c46-27-15-17-28(18-16-27)61-35-21-19-32-39-29(35)9-7-10-30(39)42(57)51(43(32)58)26-25-49-37(54)14-4-3-13-36(53)48-24-6-2-1-5-23-47-33-12-8-11-31-40(33)45(60)52(44(31)59)34-20-22-38(55)50-41(34)56/h7-12,15-19,21,34,47H,1-6,13-14,20,22-26H2,(H,48,53)(H,49,54)(H,50,55,56)
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| Chemical Name |
N'-[2-[6-(4-bromophenyl)sulfanyl-1,3-dioxobenzo[de]isoquinolin-2-yl]ethyl]-N-[6-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]hexyl]hexanediamide
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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: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| 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) |
DMSO : ~50 mg/mL (~54.95 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (2.75 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (2.75 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.0991 mL | 5.4955 mL | 10.9909 mL | |
| 5 mM | 0.2198 mL | 1.0991 mL | 2.1982 mL | |
| 10 mM | 0.1099 mL | 0.5495 mL | 1.0991 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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