| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
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| 5mg |
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| 10mg |
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| Other Sizes |
| Targets |
BRD2 1.1 nM (IC50) BRD2 186 nM (Kd) BRD3 BRD4
SIM1 targets the BET family of epigenetic reader proteins, specifically BRD2, BRD3, and BRD4. As a trivalent PROTAC based on VHL, it binds simultaneously to the target protein and the VHL E3 ligase. It demonstrates a strong preference for degrading BRD2, with a DC50 of 1.1 nM in HEK293 cells, and also degrades BRD3 (DC50 = 3.3 nM) and BRD4 (DC50 = 0.7 nM). Its binding affinity (Kd) for BRD2 is 186 nM. |
|---|---|
| ln Vitro |
After six hours, SIM1 (1 nM; 30 hours; MV4-11 cells) produces detectable cell death [1]. BET proteins breakdown in 4 hours with 1 μM of SIM1 in HEK293 cells [1]. When SIM1 binds to the BET protein, it undergoes a conformational shift that results in the simultaneous, highly affinic binding of both of its bromodomains in a cis intramolecular fashion. In order to create a 1:1:1 ternary complex with VHL and BRD4, SIM1 intramolecularly binds BD1 and BD2 [1].
In vitro, SIM1 potently inhibits the viability of MV4-11 acute myeloid leukemia (AML) cells with an IC50 of 1.1 nM at 48 hours. It decreases protein levels of MYC and HMOX1 and induces apoptosis in prostate cancer cells. SIM1 shows more efficacious apoptosis-induced cytotoxicity in BET-sensitive cancer cell lines than bivalent PROTACs or standard inhibitors, demonstrating a superior and sustained anticancer activity. |
| ln Vivo |
While detailed in vivo efficacy data from xenograft studies is not extensively detailed in the provided literature, its potent in vitro activity and validated mechanism of action strongly support its potential for anti-tumor activity in animal models. As a highly potent degrader, it is expected to be used in mouse xenograft models to evaluate its ability to degrade BET proteins and inhibit tumor growth in vivo.
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| Enzyme Assay |
For a cell-free system, the binding affinity of SIM1 to its target is measured using a fluorescence polarization (FP) competition assay. Recombinant BRD2 protein is incubated with a fluorescently labeled peptide. The compound is added to compete, and the decrease in polarization is measured. The DC50 values for degradation are determined not in cell-free assays, but by Western blot analysis of cellular lysates.
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| Cell Assay |
Cell Viability Assay[1]
Cell Types: MV4-11 cells Tested Concentrations: 1 nM Incubation Duration: 30 hrs (hours) Experimental Results: Resulted in measurable cellular death after 6 hrs (hours). Western Blot Analysis[1] Cell Types: HEK293 cells Tested Concentrations: 1 µM Incubation Duration: 4 hrs (hours) Experimental Results: Degraded BET proteins. In cellular assays, cell lines such as HEK293 or MV4-11 are seeded in multi-well plates. They are treated with serial dilutions of SIM1 (e.g., 1 nM to 10 uM) for 24 to 72 hours. After treatment, cells are harvested, and the levels of BET proteins (BRD2, BRD3, BRD4) are analyzed by Western blotting to determine the DC50 values. Cell viability is concurrently assessed using a luminescence-based CellTiter-Glo assay. |
| Animal Protocol |
For in vivo studies, SIM1 can be formulated in a vehicle such as 5% DMSO + 40% PEG300 + 5% Tween-80 + 50% ddH2O or in a 10% DMSO + 90% (20% SBE-beta-CD in Saline) solution. The compound is typically administered via intraperitoneal (IP) injection to tumor-bearing mice. Tumor volume is measured with calipers to assess anti-tumor efficacy, and tumor tissues are harvested post-study for Western blot analysis to confirm target degradation.
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| ADME/Pharmacokinetics |
Specific ADME (absorption, distribution, metabolism, and excretion) data for SIM1 is not provided in the standard literature. However, as a trivalent PROTAC, its molecular weight (approximately 1.5 kDa) typically results in lower oral bioavailability, making intraperitoneal (IP) or intravenous (IV) administration the preferred routes for in vivo studies. Its solubility in the standard formulation (5 mg/mL in 10% DMSO, 40% PEG300, 5% Tween-80, 45% saline) suggests it is suitable for such injections.
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| Toxicity/Toxicokinetics |
No specific toxicology data for SIM1 is presented in the provided literature. As a potent degrader of all BET family members, its on-target toxicity is expected to be correlated with its pharmacological activity. BET proteins are critical for the expression of various genes, including those involved in cell cycle progression and immune function. Its safety profile is an active area of investigation in preclinical research.
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| References | |
| Additional Infomation |
SIM1 is a groundbreaking trivalent PROTAC that represents a significant advancement in targeted protein degradation technology. By simultaneously binding to BRD2, BRD3, and BRD4, it overcomes the limitations of bivalent PROTACs and demonstrates superior activity. Its mechanism of action involves inducing a ternary complex with VHL, leading to potent and sustained degradation of BET proteins. SIM1 is exclusively a preclinical research tool and is not approved for any clinical use.
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| Molecular Formula |
C79H98CL2N14O13S3
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|---|---|
| Molecular Weight |
1618.81
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| Exact Mass |
1616.597
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| CAS # |
2719051-84-8
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| PubChem CID |
156022820
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| Appearance |
White to light yellow solid powder
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| Density |
1.39±0.1 g/cm3(Predicted)
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| LogP |
8.1
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| Hydrogen Bond Donor Count |
5
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| Hydrogen Bond Acceptor Count |
23
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| Rotatable Bond Count |
39
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| Heavy Atom Count |
111
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| Complexity |
2920
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| Defined Atom Stereocenter Count |
5
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| SMILES |
ClC1C=CC(=CC=1)C1C2C(C)=C(C)SC=2N2C(C)=NN=C2[C@H](CC(NCCOCCOCCOCC(C)(COCCOCCOCCNC(C[C@H]2C3=NN=C(C)N3C3=C(C(C)=C(C)S3)C(C3C=CC(=CC=3)Cl)=N2)=O)COCC(N[C@H](C(N2C[C@@H](C[C@H]2C(NCC2C=CC(C3=C(C)N=CS3)=CC=2)=O)O)=O)C(C)(C)C)=O)=O)N=1
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| InChi Key |
RARNTROXRCXFHV-CMRSQZKGSA-N
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| InChi Code |
InChI=1S/C79H98Cl2N14O13S3/c1-46-49(4)110-76-66(46)68(54-16-20-57(80)21-17-54)86-60(72-91-89-51(6)94(72)76)37-63(97)82-24-26-102-28-30-104-32-34-106-42-79(11,44-108-41-65(99)88-71(78(8,9)10)75(101)93-40-59(96)36-62(93)74(100)84-39-53-12-14-56(15-13-53)70-48(3)85-45-109-70)43-107-35-33-105-31-29-103-27-25-83-64(98)38-61-73-92-90-52(7)95(73)77-67(47(2)50(5)111-77)69(87-61)55-18-22-58(81)23-19-55/h12-23,45,59-62,71,96H,24-44H2,1-11H3,(H,82,97)(H,83,98)(H,84,100)(H,88,99)/t59-,60+,61+,62+,71-/m1/s1
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| Chemical Name |
(2S,4R)-1-[(2S)-2-[[2-[3-[2-[2-[2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]ethoxy]ethoxy]-2-[2-[2-[2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]ethoxy]ethoxymethyl]-2-methylpropoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide
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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: (1). This product requires protection from light (avoid light exposure) during transportation and storage. (2). 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: 100 mg/mL (61.77 mM)
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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 | 0.6177 mL | 3.0887 mL | 6.1774 mL | |
| 5 mM | 0.1235 mL | 0.6177 mL | 1.2355 mL | |
| 10 mM | 0.0618 mL | 0.3089 mL | 0.6177 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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