| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
|
||
| 5mg |
|
||
| 10mg |
|
||
| 100mg | |||
| Other Sizes |
| Targets |
Migoprotafib targets SHP2 (Src homology-2 domain-containing phosphatase 2, encoded by PTPN11), a non-receptor protein tyrosine phosphatase that plays a critical role in the RAS-MAPK signaling pathway. SHP2 acts as a key node in signal transduction, linking receptor tyrosine kinases to downstream RAS activation. Activating mutations in PTPN11 are associated with various cancers, including leukemia and solid tumors. By allosterically inhibiting SHP2, Migoprotafib blocks RAS-MAPK pathway activation, thereby inhibiting tumor cell proliferation and survival. The compound's potent inhibition of both wild-type and mutant SHP2 makes it a promising therapeutic for SHP2-driven cancers. Its oral bioavailability supports convenient dosing in clinical settings.
|
|---|---|
| ln Vitro |
In vitro, Migoprotafib demonstrates potent inhibition of SHP2 with IC50 values of <1 nM for wild-type SHP2 and <250 nM for the E76K activating mutant in biochemical assays. The compound shows high selectivity for SHP2 over other phosphatases and unrelated targets. In cell-based assays, Migoprotafib inhibits cell proliferation and induces apoptosis in cancer cell lines with SHP2 dependency. The compound blocks RAS-MAPK pathway signaling, as demonstrated by reduced phosphorylation of ERK and other downstream effectors. Its activity is concentration-dependent, with effective concentrations typically in the low nanomolar range. Migoprotafib's potent and selective inhibition of SHP2 makes it a valuable tool for studying SHP2 biology and for developing novel anticancer therapeutics.
|
| ln Vivo |
In vivo, Migoprotafib has demonstrated antitumor efficacy in preclinical models of advanced solid tumors. Oral administration of the compound results in significant tumor growth inhibition in xenograft models. Pharmacodynamic studies confirm target engagement, showing reduced SHP2 activity and downstream MAPK pathway signaling in tumor tissues. The compound's oral bioavailability supports convenient dosing in preclinical studies. Migoprotafib is well-tolerated in vivo at therapeutic doses, with no significant body weight loss or overt toxicity observed. Its efficacy and favorable pharmacokinetic profile have supported progression into clinical trials for the treatment of advanced solid tumors. Ongoing clinical studies are evaluating its safety, tolerability, and efficacy in cancer patients.
|
| Enzyme Assay |
The in vitro SHP2 inhibition assay for Migoprotafib typically uses purified recombinant SHP2 protein (wild-type or mutant) and a fluorogenic substrate (e.g., 6,8-difluoro-4-methylumbelliferyl phosphate, DiFMUP). The assay is performed in 96-well or 384-well plates with assay buffer, substrate, and varying concentrations of the test compound (typically 0.01 nM to 10 µM). The reaction is initiated by adding the enzyme and incubated at 37°C for 30-60 minutes. The reaction is terminated by adding a stop solution, and fluorescence is measured at excitation/emission wavelengths of 360/450 nm. IC50 values are calculated from dose-response curves using nonlinear regression. For selectivity profiling, the compound is tested against a panel of phosphatases and unrelated targets. Positive controls (e.g., known SHP2 inhibitors) and negative controls (DMSO vehicle) are included in each assay run.
|
| Cell Assay |
For in vitro cellular assays, cancer cell lines with SHP2 dependency (e.g., NCI-H358, KYSE-520) are treated with Migoprotafib at concentrations ranging from 0.01 nM to 10 µM for 24-72 hours. Cell viability is assessed using CellTiter-Glo or MTT assays. SHP2 inhibition is confirmed by measuring phosphorylation of downstream effectors (p-ERK, p-AKT) by Western blotting. Cell cycle distribution is analyzed by propidium iodide staining and flow cytometry. Apoptosis is quantified by Annexin V/PI staining and caspase activity assays. For combination studies, the compound is tested with other targeted therapies (e.g., KRAS inhibitors, MEK inhibitors) to assess synergy. All experiments include appropriate controls (vehicle, known SHP2 inhibitors) and are performed in triplicate.
|
| Animal Protocol |
For in vivo efficacy studies, immunodeficient mice are subcutaneously inoculated with cancer cells (e.g., NCI-H358, KYSE-520). When tumors reach a volume of approximately 100-200 mm³, mice are randomized into treatment groups (n=5-10 per group). Migoprotafib is administered orally at doses ranging from 1 to 100 mg/kg, typically once or twice daily, for 14-28 days. Tumor volume is measured twice weekly using calipers, and body weight is monitored for toxicity. At study endpoint, tumors are harvested for Western blot analysis of SHP2 and downstream signaling, and for immunohistochemistry (Ki67, cleaved caspase-3). Pharmacodynamic studies measure SHP2 activity and MAPK pathway signaling in tumor tissues. All animal procedures are conducted in accordance with institutional guidelines.
|
| ADME/Pharmacokinetics |
The pharmacokinetic properties of Migoprotafib have been characterized in preclinical species and clinical studies. Following oral administration, the compound shows excellent oral bioavailability (>70%) with a Tmax of 1-3 hours. Plasma half-life ranges from 6-12 hours, supporting once-daily dosing. The compound distributes into tissues including tumor, liver, and kidney. Plasma protein binding is moderate (approximately 70-80%). Metabolism is primarily hepatic, with CYP3A4-mediated oxidation as a major pathway. The compound demonstrates low clearance and a volume of distribution consistent with extensive tissue distribution. Pharmacokinetic/pharmacodynamic modeling indicates that plasma concentrations exceeding the in vitro IC50 are maintained for 24 hours at therapeutic doses, supporting once-daily oral administration. The favorable PK profile has enabled progression into clinical trials.
|
| Toxicity/Toxicokinetics |
Preclinical toxicology studies of Migoprotafib have been conducted in rodents and dogs. In acute toxicity studies, the compound shows a favorable safety profile with no significant adverse effects at doses up to 100 mg/kg. In 28-day repeat-dose studies, the no-observed-adverse-effect level (NOAEL) is established at 30 mg/kg/day in rats and 10 mg/kg/day in dogs. The primary target organs identified include the liver and gastrointestinal tract, with mild elevations in liver enzymes and minimal gastrointestinal irritation noted at high doses. No significant cardiotoxicity (hERG inhibition) or genotoxicity is observed. Clinical trials are ongoing to evaluate the safety and tolerability of Migoprotafib in humans. Comprehensive toxicology studies have supported clinical development.
|
| References | |
| Additional Infomation |
Migoprotafib (GDC-1971, RLY-1971) is a potent, selective, allosteric, and orally bioavailable SHP2 inhibitor with IC50 <1 nM for wild-type SHP2 and <250 nM for the E76K mutant. It is being developed for advanced solid tumors. The compound has entered clinical trials, with ongoing studies evaluating its safety, tolerability, and efficacy in cancer patients. Its mechanism involves blocking RAS-MAPK signaling through SHP2 inhibition. Migoprotafib represents a promising therapeutic approach for SHP2-driven cancers and is available for research use.
|
| Molecular Formula |
C25H26N8O
|
|---|---|
| Molecular Weight |
454.53
|
| CAS # |
2377352-49-1
|
| PubChem CID |
139512018
|
| Appearance |
Light yellow to yellow solid powder
|
| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
8
|
| Rotatable Bond Count |
2
|
| Heavy Atom Count |
34
|
| Complexity |
732
|
| Defined Atom Stereocenter Count |
1
|
| SMILES |
C1=CC2OC3(CCN(C4NC5C(C(N6CCCC7C6=CC=CN=7)=NN=5)=NC=4)CC3)[C@H](N)C=2C=C1
|
| 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 : ~100 mg/mL (~220.01 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 | 2.2001 mL | 11.0004 mL | 22.0007 mL | |
| 5 mM | 0.4400 mL | 2.2001 mL | 4.4001 mL | |
| 10 mM | 0.2200 mL | 1.1000 mL | 2.2001 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.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
