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| Targets |
Migoprotafib targets SHP2 (Src Homology-2 Domain-Containing Phosphatase 2), a non-receptor protein tyrosine phosphatase that plays a critical role in the RAS/MAPK signaling pathway. SHP2 acts as a key node connecting RTK signaling to downstream RAS activation. Migoprotafib binds and stabilizes SHP2 in its inactive conformation, thereby blocking its phosphatase activity and inhibiting downstream RAS/MAPK pathway signaling. This allosteric mechanism provides selectivity over other phosphatases.
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| ln Vitro |
In vitro, Migoprotafib potently inhibits cellular proliferation in models harboring RTK, SHP2, NF1, KRAS, or BRAF mutations in a dose-dependent manner. It potently inhibits the proliferation of cellular models harboring KRAS G12C or G12A mutations with a median IC50 <80 nM, compared to models harboring other KRAS mutations with a median IC50 >1 µM. It demonstrates increased suppression of MAPK signaling and anti-proliferation synergy when combined with EGFR, ALK, and KRAS G12C inhibitors.
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| ln Vivo |
In vivo, Migoprotafib demonstrates dose-dependent RAS/MAPK pathway inhibition and induces significant tumor growth inhibition in human xenograft models harboring EGFR and KRAS alterations. It exhibits dramatic synergistic anti-tumor growth effects when combined with the KRAS G12C covalent inhibitor GDC-6036. The compound is orally bioavailable. These in vivo efficacy data support its clinical development for RTK/RAS-driven cancers.
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| Enzyme Assay |
For SHP2 biochemical assays, recombinant wild-type or mutant SHP2 protein is incubated with a fluorogenic phosphatase substrate (such as 6,8-difluoro-4-methylumbelliferyl phosphate, DiFMUP) in assay buffer at room temperature. The test compound is added at various concentrations (typically 0.001-10 µM). Fluorescence is measured at excitation 360 nm and emission 460 nm over time to determine initial reaction rates. IC50 values are calculated by fitting dose-response curves.
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| Cell Assay |
For cell proliferation assays, cancer cell lines harboring various RTK, SHP2, NF1, KRAS, or BRAF mutations are seeded in 96-well plates and treated with Migoprotafib at concentrations ranging from 0.001-10 µM for 72-96 hours. Cell viability is assessed using CellTiter-Glo or MTT assays. IC50 values are calculated from dose-response curves. For combination studies, cells are treated with Migoprotafib plus EGFR, ALK, or KRAS G12C inhibitors, and synergy is assessed using the Bliss independence or Chou-Talalay methods.
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| Animal Protocol |
For in vivo efficacy studies, immunodeficient mice are subcutaneously implanted with human tumor xenografts harboring EGFR or KRAS alterations. When tumors reach approximately 100-200 mm³, mice are randomized and treated orally with Migoprotafib at doses determined from PK studies. Tumor volumes are measured twice weekly. At study endpoint, tumors are collected for Western blot analysis of phospho-ERK and other MAPK pathway markers to confirm target inhibition. Combination studies with KRAS G12C inhibitors are performed to evaluate synergy in vivo.
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| ADME/Pharmacokinetics |
Migoprotafib is orally bioavailable. It shows favorable pharmacokinetic properties suitable for once-daily oral dosing. The compound is soluble in DMSO at 10 mM. Powdered form can be stored at -20°C for 12 months and at 4°C for 6 months; solutions can be stored at -80°C for 6 months or -20°C for 6 months. Further detailed PK parameters (half-life, Cmax, AUC, protein binding) would be available in the primary literature.
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| Toxicity/Toxicokinetics |
Toxicology data for Migoprotafib would be detailed in preclinical and clinical study reports. As a clinical-stage compound, it has undergone extensive safety evaluation. Common adverse effects associated with SHP2 inhibition may include gastrointestinal disturbances, fatigue, and potential effects on hematopoiesis given the role of SHP2 in cytokine signaling. Specific toxicity data are proprietary and would be available in regulatory submissions and clinical trial disclosures.
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| References | |
| Additional Infomation |
Migoprotafib (GDC-1971) is a potent, selective, allosteric, orally bioavailable SHP2 inhibitor that is under clinical investigation for the treatment of advanced solid tumors. It inhibits wild-type SHP2 with IC50 <1 nM and E76K mutant with IC50 <250 nM. The compound blocks RAS/MAPK signaling and shows synergy with EGFR, ALK, and KRAS G12C inhibitors. It has demonstrated significant tumor growth inhibition in xenograft models harboring EGFR and KRAS alterations. Migoprotafib is a clinical-stage investigational drug and is not yet approved for therapeutic use.
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| Molecular Formula |
C25H26N8O
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|---|---|
| Molecular Weight |
454.53
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| Exact Mass |
454.222
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| CAS # |
2377352-49-1
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| PubChem CID |
139512018
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
2.4
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
34
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| Complexity |
732
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C1=CC2OC3(CCN(C4NC5C(C(N6CCCC7C6=CC=CN=7)=NN=5)=NC=4)CC3)[C@H](N)C=2C=C1
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| InChi Key |
RGCGBFIARQENML-JOCHJYFZSA-N
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| InChi Code |
InChI=1S/C25H26N8O/c26-22-16-5-1-2-8-19(16)34-25(22)9-13-32(14-10-25)20-15-28-21-23(29-20)30-31-24(21)33-12-4-6-17-18(33)7-3-11-27-17/h1-3,5,7-8,11,15,22H,4,6,9-10,12-14,26H2,(H,29,30,31)/t22-/m1/s1
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| Chemical Name |
(3R)-1'-[3-(3,4-dihydro-2H-1,5-naphthyridin-1-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]spiro[3H-1-benzofuran-2,4'-piperidine]-3-amine
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| Synonyms |
Migoprotafib; GDC-1971; GDC 1971; GDC1971; 2377352-49-1; RG6433; ABR1HZ0ZG8; .
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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 : ~100 mg/mL (~220.01 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 | 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.
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