| Size | Price | Stock | Qty |
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| 1mg |
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| Other Sizes |
| Targets |
The primary target is SHP2 (PTPN11), a key signaling node that relays signals from receptor tyrosine kinases (RTKs) to the downstream RAS-ERK MAP kinase pathway. SHP2-D26 is a PROTAC that simultaneously binds to SHP2 (via a warhead) and the E3 ubiquitin ligase VHL-1. This binding induces the ubiquitination and subsequent proteasomal degradation of the SHP2 protein, thereby eliminating both its catalytic and scaffolding functions.
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| ln Vitro |
SHP2-D26 (0, 3, 10, 30, 100, and 300 nM; 12 hours) efficiently and dose-dependently decreased SHP2 protein in KYSE520 and MV-4-11 cells, with DC50 values of 2.6 nM and 6.0 nM, respectively [1]. In KYSE520 and MV-4-11 cells, SHP2-D26 (100 nM; 0, 2, 4, 8, 12, 24 hours) decreases SHP2 protein levels in 4 hours and finishes SHP2 depletion in 8 hours [1]. For KYSE520 and MV-4-11 cells, the IC50 values of SHP2-D26 (0-100 μM and 0-10 nM, respectively; 4 days) are 0.66 μM and 0.99 nM, respectively[1].
SHP2-D26 potently induces SHP2 protein degradation with DC50 values of 6.0 nM in KYSE520 esophageal cancer cells and 2.6 nM in MV4;11 acute myeloid leukemia cells. This degradation is highly selective and strictly dependent on the neddylation and proteasome pathways. The compound is >30-times more potent in inhibiting ERK phosphorylation and cell growth than the potent SHP2 catalytic inhibitor SHP099 in these cancer cell lines. |
| ln Vivo |
Specific in vivo efficacy data for SHP2-D26 is not detailed. As a highly potent degrader with superior cellular activity, it is expected to show strong anti-tumor efficacy in mouse xenograft models of cancers driven by SHP2, such as KRAS-mutant or RTK-driven tumors. A typical protocol would involve intravenous or intraperitoneal administration of the PROTAC to tumor-bearing mice to assess tumor growth inhibition and SHP2 degradation in tumor tissue.
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| Enzyme Assay |
The biochemical activity is measured by its ability to induce the formation of a ternary complex between SHP2, VHL-1, and the PROTAC. This is typically done using an AlphaScreen assay. Purified GST-tagged VHL-1 complex is mixed with biotinylated SHP2 protein and varying concentrations of SHP2-D26. After adding AlphaScreen donor and acceptor beads, the signal is measured to determine the compound's ability to bridge these two proteins (EC50 for ternary complex formation).
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| Cell Assay |
Cell proliferation assay[1]
Cell Types: KYSE520 and MV-4-11 Cell Tested Concentrations: 0-100 μM for KYSE520 cells; 0-10 nM for MV-4-11 cells Incubation Duration: 4 days Experimental Results: KYSE520 and MV-4 The IC50 values in -11 cells were 0.66 μM and 0.99 nM respectively. Western Blot Analysis[1] Cell Types: KYSE520 and MV-4-11 Cell Tested Concentrations: 0, 3, 10, 30, 100, 300 nM Incubation Duration: 12 hrs (hours) Experimental Results: SHP2 protein diminished in a dose-dependent manner with DC50 values of 6.0 and 2.6 nM in KYSE520 and MV-4-11 cells, respectively. Western Blot Analysis[1] Cell Types: KYSE520 and MV-4-11 Cell Tested Concentrations: 100 nM Incubation Duration: 0, 2, 4, 8, 12, 24 hrs (hours) Experimental Results: diminished SHP2 protein levels and completed SHP2 removal within 4 hrs (hours)8 Hour. Cellular degradation assays are performed in KYSE520 (esophageal squamous cell carcinoma) or MV4;11 (AML) cells. Cells are treated with varying concentrations of SHP2-D26 (0.1-1000 nM) for 6-16 hours. After treatment, cells are lysed, and the levels of SHP2 protein are quantified by Western blot using a specific SHP2 antibody. DC50 values are calculated. To assess functional activity, cells are treated with the compound, and the phosphorylation of ERK (p-ERK) is measured as a proxy for downstream signaling activity. Cell viability is measured after 3-5 days of treatment using an MTT or CellTiter-Glo assay. |
| Animal Protocol |
In an in vivo study, it is standard to use a xenograft mouse model of cancer driven by a KRAS mutation or RTK overexpression (e.g., KYSE520). Female nude mice bearing established tumors (~150 mm3) are randomized into treatment groups. SHP2-D26 is administered intravenously (e.g., at 10 mg/kg) or intraperitoneally daily. Tumor volume is measured by calipers. At the end of the study (e.g., 21 days), tumors are excised and analyzed by Western blot to confirm SHP2 degradation and p-ERK suppression in the tumor tissue.
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| ADME/Pharmacokinetics |
Specific quantitative PK parameters for SHP2-D26 are not detailed. As a PROTAC with a molecular weight of 1115.89 g/mol, its design likely focuses on optimizing cellular permeability and achieving sufficient systemic exposure for protein degradation in vivo. The compound's stability in plasma, route of clearance, and tissue distribution are critical factors for its in vivo efficacy.
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| Toxicity/Toxicokinetics |
Specific toxicological data for SHP2-D26 are not detailed. As a potent degrader of a key signaling protein, its safety profile would need to be carefully evaluated. On-target toxicity might arise from the complete ablation of SHP2 function in normal tissues, which could impact hematopoietic stem cell quiescence or other developmental pathways. Standard toxicological endpoints would be assessed in animal models.
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| References | |
| Additional Infomation |
SHP2-D26 is a groundbreaking, research-grade PROTAC degrader for SHP2. It is the first reported PROTAC for this target. By degrading SHP2 rather than simply inhibiting its phosphatase activity, the compound potentially overcomes adaptive resistance mechanisms and provides a new chemical biology tool for studying SHP2 function. As of the latest updates, it is in the pre-clinical research phase and not yet approved for clinical use.
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| Molecular Formula |
C56H79CLN12O6S2
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|---|---|
| Molecular Weight |
1115.88626885414
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| Exact Mass |
1114.537
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| CAS # |
2458219-65-1
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| PubChem CID |
155930583
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
6.2
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| Hydrogen Bond Donor Count |
6
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| Hydrogen Bond Acceptor Count |
15
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| Rotatable Bond Count |
23
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| Heavy Atom Count |
77
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| Complexity |
1920
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| Defined Atom Stereocenter Count |
4
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| SMILES |
C(N1C[C@H](O)C[C@H]1C(=O)N[C@H](C1C=CC(C2=C(N=CS2)C)=CC=1)C)(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCN1CCN(C(=O)CCC(=O)NC2C=CC=C(SC3=NC=C(N4CCC(N)(C)CC4)N=C3N)C=2Cl)CC1
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| InChi Key |
XJSPAQRZSJUBLB-WQFCSRJTSA-N
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| InChi Code |
InChI=1S/C56H79ClN12O6S2/c1-36(38-17-19-39(20-18-38)49-37(2)61-35-76-49)62-52(74)42-32-40(70)34-69(42)54(75)50(55(3,4)5)65-45(71)16-11-9-7-8-10-12-25-66-28-30-68(31-29-66)47(73)22-21-46(72)63-41-14-13-15-43(48(41)57)77-53-51(58)64-44(33-60-53)67-26-23-56(6,59)24-27-67/h13-15,17-20,33,35-36,40,42,50,70H,7-12,16,21-32,34,59H2,1-6H3,(H2,58,64)(H,62,74)(H,63,72)(H,65,71)/t36-,40+,42-,50+/m0/s1
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| Chemical Name |
(2S,4R)-1-[(2S)-2-[9-[4-[4-[3-[3-amino-5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl]sulfanyl-2-chloroanilino]-4-oxobutanoyl]piperazin-1-yl]nonanoylamino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]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 |
| 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 : ~83.33 mg/mL (~74.68 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 | 0.8961 mL | 4.4807 mL | 8.9615 mL | |
| 5 mM | 0.1792 mL | 0.8961 mL | 1.7923 mL | |
| 10 mM | 0.0896 mL | 0.4481 mL | 0.8961 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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