| Size | Price | Stock | Qty |
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| 1mg |
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| Other Sizes |
| Targets |
IC50: 1.9 nM (SHP2)[1]
JAB-3312 targets SHP2 (PTPN11), a non-receptor protein tyrosine phosphatase that acts downstream of multiple receptor tyrosine kinases (RTKs) and is a key node in the RAS-MAPK signaling pathway. It functions as a molecular switch to transduce signals for cell survival, proliferation, and differentiation. JAB-3312 binds to an allosteric pocket in the closed, auto-inhibited conformation of SHP2, preventing its activation and subsequent downstream signaling. It has been studied in combination with KRAS G12C inhibitors (e.g., in NSCLC) and in esophageal squamous cell carcinoma (ESCC) and head and neck squamous cell carcinoma (HNSCC). |
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| ln Vitro |
In vitro, JAB-3312 is a potent and selective SHP2 inhibitor with an IC₅0 of 1.9 nM and a Kd of 0.37 nM. It is inactive in inhibiting 22 other phosphatases (including SHP1 and the PTP domain of SHP2) and 25 kinases, confirming its high selectivity. In KYSE-520 (ESCC) cell proliferation assays (MTT, 72 h), it inhibits cell growth with an IC₅0 of 50-150 nM. It also inhibits ERK1/2 phosphorylation (p-ERK) in a dose-dependent manner at 10-100 nM. In NSCLC cells with KRAS G12C mutations (e.g., NCI-H358), JAB-3312 (0.1-1000 nM) inhibits p-ERK with an IC₅0 of 5-20 nM.
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| ln Vivo |
In vivo, JAB-3312 is orally active and has good tolerability. In a mouse xenograft model of KYSE-520 (esophageal squamous cell carcinoma), JAB-3312 (10-50 mg/kg, oral, once daily for 14-21 days) significantly induces tumor regression. In combination with a KRAS G12C inhibitor (e.g., sotorasib, 30 mg/kg), JAB-3312 enhances anti-tumor efficacy and prevents or delays resistance to KRAS inhibition. In lung metastasis models (e.g., H358 cells in NSG mice), JAB-3312 (50 mg/kg, oral, daily) reduces lung tumor burden.
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| Enzyme Assay |
For SHP2 enzymatic activity assays, recombinant human SHP2 (1-10 nM) is incubated with JAB-3312 (0.01-1000 nM) in assay buffer (50 mM HEPES pH 7.5, 100 mM NaCl, 5 mM DTT, 1 mM EDTA, 0.01% Brij-35) for 15-30 min. A fluorogenic peptide substrate (e.g., DiFMUP or 6,8-difluoro-4-methylumbelliferyl phosphate, 10-100 uM) is added, and the reaction is incubated at 30degC for 30-60 min. Fluorescence (Ex/Em 360/460 nm) is measured, and IC₅0 is calculated. For selectivity, the compound is tested against a panel of 22 phosphatases and 25 kinases at 100 nM. For binding affinity (Kd), a TR-FRET binding assay (using a fluorescently labeled SHP2 probe) or SPR (surface plasmon resonance) is used.
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| Cell Assay |
For cellular assays, cancer cells (KYSE-520, H358) are seeded in 6-well plates (2-5 × 10⁵ cells/well) and treated with JAB-3312 (0.1-1000 nM) for 2-4 h. Cells are lysed in RIPA buffer with protease and phosphatase inhibitors. Protein lysates (20-50 ug) are separated by SDS-PAGE and Western blotted for p-SHP2, total SHP2, p-ERK (Thr202/Tyr204), total ERK, and GAPDH (loading control). Apoptosis is assessed by Annexin V/PI staining after 48-72 hours. Cell cycle is analyzed by propidium iodide staining and flow cytometry. For proliferation assays (MTT or CellTiter-Glo, 96-well plates, 5,000 cells/well, 72 h treatment), IC₅0 values are calculated (KYSE-520 IC₅0: 50-150 nM). For combination studies, JAB-3312 (1-100 nM) is combined with a KRAS G12C inhibitor (0.1-100 nM), and synergy is determined by the Chou-Talalay combination index (CI <1).
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| Animal Protocol |
For in vivo xenograft studies, female BALB/c nude mice (6-8 weeks, 18-22 g, n=8-10 per group) are inoculated subcutaneously (SC) with 5 × 10⁶ KYSE-520 cells (or H358 KRAS G12C cells) in 100 uL of PBS mixed with 100 uL Matrigel. When tumors reach 150-200 mm3, mice are randomized. JAB-3312 is formulated in 5% DMSO, 40% PEG300, 5% Tween-80, 50% ddH2O. Mice receive JAB-3312 at 10-50 mg/kg by oral gavage once daily for 14-21 days. For combination, JAB-3312 (10 mg/kg, oral) + sotorasib (30 mg/kg, oral) is administered. Tumor volumes are measured every 2-3 days with calipers. Body weight is monitored for toxicity. At the end of the study, tumors are excised for Western blot (p-ERK, p-SHP2) and immunohistochemistry (Ki-67, cleaved caspase-3). For lung metastasis models, H358-luc cells (1 × 10⁶) are injected IV (tail vein). JAB-3312 (50 mg/kg, oral, daily) is given for 14-28 days. Lung tumor burden is monitored by IVIS imaging (bioluminescence). Survival is recorded as the end point. All IACUC guidelines apply.
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| ADME/Pharmacokinetics |
JAB-3312 is orally bioavailable (F ~30-60%). After oral administration in mice (10-50 mg/kg), Tmax is 1-2 hours, and the elimination half-life (t½) is 4-8 hours. Plasma protein binding is high (>90%). Solubility in DMSO is 100 mg/mL. It is metabolized primarily by CYP3A4 and excreted in feces. Not for human use.
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| Toxicity/Toxicokinetics |
JAB-3312 is well tolerated in preclinical studies at doses up to 50 mg/kg. No significant body weight loss or hepatotoxicity (ALT/AST elevation) is reported. No genotoxicity. The most common adverse events in clinical trials (Phase 1) are mild to moderate (nausea, fatigue, rash). Not for human use outside clinical trials.
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| References | |
| Additional Infomation |
Sitneprotafib is an orally bioavailable allosteric inhibitor of protein tyrosine phosphatase (PTP) non-receptor type 11 (SHP2; Src homeo domain 2 phosphatase; PTPN11) with potential antitumor activity. After oral administration, ceteponepib targets and binds to SHP2 activity. This blocks SHP2-mediated signaling, inhibits MAPK signaling, and suppresses the growth of SHP2-expressing tumor cells. SHP2 is an oncoprotein overexpressed in various cancer cell types that regulates cell survival, differentiation, and proliferation by activating the Ras-Raf-MEK-ERK signaling pathway. The Ras-MAPK pathway is often overactivated in cancer cells due to specific mutations and rearrangements that depend on SHP2 for oncogenic signaling. SHP2 also regulates programmed cell death 1 (PD-1)-mediated signaling and is involved in immune checkpoint regulation.
JAB-3312 is an investigational drug in clinical development (Phase 1/2) for KRAS G12C-mutant NSCLC, esophageal squamous cell carcinoma, and head and neck squamous cell carcinoma. It is not an FDA-approved drug. It has received Orphan Drug Designation (status may vary). For research use only. |
| Molecular Formula |
C21H22CLN7S
|
|---|---|
| Molecular Weight |
439.96
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| Exact Mass |
439.135
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| CAS # |
2245082-05-5
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| PubChem CID |
142434183
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| Appearance |
White to off-white solid powder
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| Density |
1.48±0.1 g/cm3(Predicted)
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| Boiling Point |
668.0±55.0 °C(Predicted)
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| LogP |
0
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| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
8
|
| Rotatable Bond Count |
3
|
| Heavy Atom Count |
30
|
| Complexity |
590
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C12CC3(CCN(C4=NC=C(SC5C=CN=C(N)C=5Cl)N=C4)CC3)[C@H](N)C1=CC=CN=2
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| InChi Key |
GKGIGIUNYOFYHZ-LJQANCHMSA-N
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| InChi Code |
InChI=1S/C21H22ClN7S/c22-18-15(3-7-26-20(18)24)30-17-12-27-16(11-28-17)29-8-4-21(5-9-29)10-14-13(19(21)23)2-1-6-25-14/h1-3,6-7,11-12,19H,4-5,8-10,23H2,(H2,24,26)/t19-/m1/s1
|
| Chemical Name |
(5S)-1'-[5-[(2-amino-3-chloro-4-pyridinyl)sulfanyl]pyrazin-2-yl]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-5-amine
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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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 | 2.2729 mL | 11.3647 mL | 22.7293 mL | |
| 5 mM | 0.4546 mL | 2.2729 mL | 4.5459 mL | |
| 10 mM | 0.2273 mL | 1.1365 mL | 2.2729 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.
Link: https://clinicaltrials.gov/ct2/show/NCT04045496
Conditions:Non-small Cell Lung Cancer|Colorectal Cancer|Pancreatic Ductal Carcinoma|Esophageal Squamous Cell Carcinoma|Head and Neck Squamous Cell Carcinoma|Breast Cancer|Other Solid TumorsLink: https://clinicaltrials.gov/ct2/show/NCT04121286
Conditions:Non-small Cell Lung Cancer|Colorectal Cancer|Pancreatic Ductal Carcinoma|Esophageal Squamous Cell Carcinoma|Head and Neck Squamous Cell Carcinoma|Breast Cancer|Other Solid TumorsLink: https://clinicaltrials.gov/ct2/show/NCT04720976
Conditions:Solid Tumor|NSCLC
Title:Phase 1/2a Study of JAB-21822 Plus JAB-3312 in Patients With Advanced Solid Tumors Harboring KRAS p.G12C Mutation
Status:Recruiting
updateDate:2025-04-04
Ctid:NCT05288205
Link: https://clinicaltrials.gov/ct2/show/NCT05288205
Conditions:KRAS P.G12C|Non-small Cell Lung Cancer|Colorectal Cancer|Pancreatic Ductal CarcinomaLink: https://clinicaltrials.gov/ct2/show/NCT06416410
Conditions:Advanced Non-squamous Non-small-cell Lung Cancer|Metastatic Non-squamous Non Small Cell Lung CancerProducts are for research use only; We do not sell to patients
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