| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 25mg |
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| Other Sizes |
Purity: ≥98%
| Targets |
CG428 is a first-in-class tropomyosin receptor kinase (TRK) degrader targeting TRKA, TRKB, and TRKC with high selectivity. It achieves degradation via a cereblon (CRBN)-mediated E3 ligase pathway. Key binding parameters include:
- TRKA: Degradation DC50 = 0.36 nM (in TMP3-TRKA cells) - TRKA: Kinase inhibition IC50 = 1 nM (KinomeScan assay) - TRKB: Kinase inhibition IC50 = 4.2 nM - TRKC: Kinase inhibition IC50 = 28 nM |
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| ln Vitro |
- TRK degradation: CG428 potently induced TRKA degradation in multiple cancer cell lines, including KM12 (colon cancer) and HEL (erythroleukemia). After 6-hour treatment, DC50 values were 0.36 nM (TMP3-TRKA) and 2.23 nM (TRKA in HEL cells) .
- Antiproliferative activity: Inhibited growth of TRKA-fusion-positive KM12 cells with an IC50 of 2.9 nM .
- Mechanism: Degradation was confirmed by Western blot analysis showing dose-dependent reduction of TRKA protein levels. This was accompanied by decreased phosphorylation of downstream targets like AKT and ERK .
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| Enzyme Assay |
- Kinase inhibition assay: Recombinant TRKA kinase domain was incubated with ATP and a biotinylated substrate peptide in the presence of CG428 (0.01–100 nM). Phosphorylation was detected using a luminescent ADP detection kit, yielding IC50 values. KinomeScan profiling confirmed high selectivity for TRKA over other kinases .
- Degradation assay: HEK293 cells stably expressing TMP3-TRKA were treated with CG428 (0.01–100 nM) for 6 hours. Cell lysates were analyzed by Western blot to quantify TRKA protein levels, calculating DC50 values .
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| Cell Assay |
- Proliferation inhibition: KM12 cells (5×10³/well) were treated with CG428 (0.01–10 μM) for 72 hours. Cell viability was measured using MTT reagent, with GI50 calculated as 2.9 nM .
- TRK degradation analysis: HEL cells were treated with CG428 (0.1–100 nM) for 6 hours. Western blot detected TRKA protein levels, showing complete degradation at 10 nM. Phosphorylation of AKT (Ser473) and ERK (Thr202/Tyr204) was concomitantly reduced .
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| ADME/Pharmacokinetics |
- Oral bioavailability: CG428 showed moderate oral bioavailability (F = 35%) in preclinical models, reaching peak plasma concentration (Cmax) within 1–2 hours after administration. - Plasma protein binding: Estimated plasma protein binding is >92%. - Metabolism: Primarily metabolized by hepatic cytochrome P450 enzyme (CYP3A4), with the major metabolite retaining approximately 30% of the parent activity.
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| References | |
| Additional Infomation |
Structural Design: Contains a pan-TRK inhibitor (GNF-8625 analogue) linked to a pomalidomide-based CRBN ligand, thereby achieving targeted protein degradation. - Therapeutic Potential: Demonstrates efficacy in TRKA fusion-positive solid tumors and exhibits synergistic effects when used in combination with MEK inhibitors in preclinical models. - Novel Mechanism: Represents a novel class of TRK degraders distinct from ATP-competitive inhibitors, potentially overcoming resistance mutations.
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| Molecular Formula |
C43H43FN10O6
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|---|---|
| Molecular Weight |
814.863332033157
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| Exact Mass |
814.335
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| Elemental Analysis |
C, 63.38; H, 5.32; F, 2.33; N, 17.19; O, 11.78
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| CAS # |
2412055-93-5
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| PubChem CID |
146410727
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| Appearance |
Typically exists as solid at room temperature
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| LogP |
3.5
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
13
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| Rotatable Bond Count |
12
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| Heavy Atom Count |
60
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| Complexity |
1590
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| Defined Atom Stereocenter Count |
1
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| SMILES |
FC1=CC=CC(=C1)[C@H]1CCCN1C1C=CC2=NC=C(C3=CC=CC(=N3)N3CCN(C(CCOCCNC4=CC=CC5C(N(C(C=54)=O)C4C(NC(CC4)=O)=O)=O)=O)CC3)N2N=1
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| InChi Key |
FWANKJAOTQAHHR-KWRHIPAJSA-N
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| InChi Code |
InChI=1S/C43H43FN10O6/c44-28-6-1-5-27(25-28)32-10-4-18-52(32)37-14-13-35-46-26-34(54(35)49-37)30-8-3-11-36(47-30)50-19-21-51(22-20-50)39(56)16-23-60-24-17-45-31-9-2-7-29-40(31)43(59)53(42(29)58)33-12-15-38(55)48-41(33)57/h1-3,5-9,11,13-14,25-26,32-33,45H,4,10,12,15-24H2,(H,48,55,57)/t32-,33?/m1/s1
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| Chemical Name |
2-(2,6-dioxopiperidin-3-yl)-4-[2-[3-[4-[6-[6-[(2R)-2-(3-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl]pyridin-2-yl]piperazin-1-yl]-3-oxopropoxy]ethylamino]isoindole-1,3-dione
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| Synonyms |
CG428; 2412055-93-5; CG 428; CHEMBL4798635; orb1690054; SCHEMBL21759979; SCHEMBL30502194; SCHEMBL30864553;
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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) |
Typically soluble in DMSO (e.g. 10 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 | 1.2272 mL | 6.1360 mL | 12.2720 mL | |
| 5 mM | 0.2454 mL | 1.2272 mL | 2.4544 mL | |
| 10 mM | 0.1227 mL | 0.6136 mL | 1.2272 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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