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| Targets |
PERK (EIF2AK3). PERK-IN-2 targets the kinase domain of PERK, acting as an ATP-competitive inhibitor. It specifically binds to the active site, preventing the transfer of phosphate groups to its substrate, eIF2alpha. This blockade of autophosphorylation disrupts the signal transduction pathway downstream of ER stress, thereby modulating the cellular response to unfolded proteins. The IC₅0 for PERK inhibition is 0.2 nM, demonstrating high potency.
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| ln Vitro |
With IC50 values in the range of 0.03−0.1 μM, PERK-IN-2 (0.03-0.3 μM; 2 hours) suppresses PERK autophosphorylation in A459 cells [1].
In vitro, PERK-IN-2 effectively suppresses PERK autophosphorylation in human A549 lung carcinoma cells. The IC₅0 for this cellular activity ranges from 0.03 to 0.1 microM, confirming its potent target engagement in a physiological context. At concentrations between 0.03 microM and 0.3 microM, with an exposure time of 2 hours, the compound demonstrates a dose-dependent reduction of PERK activity in intact cells, validating its cell permeability and efficacy in disrupting the ER stress signaling pathway. |
| ln Vivo |
Specific in vivo efficacy data is limited. However, literature suggests that highly efficient and selective PERK inhibitors with oral bioavailability, including PERK-IN-2, have been identified. These inhibitors are studied for their therapeutic potential in conditions like cancer where ER stress contributes to tumor cell survival. Although specific animal model data for PERK-IN-2 alone is sparse, it is presumed to inhibit PERK signaling in vivo, affecting downstream phosphorylation of eIF2alpha and subsequent protein translation.
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| Enzyme Assay |
A cell-free ELISA-based kinase activity assay is conducted. A recombinant PERK protein is incubated with ATP, a specific substrate peptide (eIF2alpha), and various concentrations of PERK-IN-2 in a kinase reaction buffer. The reaction is stopped with EDTA, and the reaction mixture is transferred to a plate coated with an anti-substrate antibody. Phosphorylation of the substrate is detected using an anti-phospho-eIF2alpha antibody followed by a chemiluminescent HRP substrate. Luminescence is measured to determine the IC₅0.
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| Cell Assay |
Cell viability assay [1]
Cell Types: A459 Cell Tested Concentrations: 0.03 μM, 0.1 μM, 0.3 μM Incubation Duration: 2 hrs (hours) Experimental Results: Inhibition of PERK autophosphorylation in A459 cells. A549 human lung carcinoma cells are seeded in 96-well plates and cultured overnight. The medium is replaced with fresh medium containing thapsigargin (an ER stress inducer) and varying concentrations of PERK-IN-2 (e.g., 0.03, 0.1, 0.3 microM) for 2 hours. Cells are then lysed, and protein concentration is normalized. The lysates are analyzed by Western blotting using antibodies specific for phospho-PERK (p-PERK) and total PERK. The signal intensities of p-PERK are normalized to total PERK to calculate autophosphorylation inhibition. |
| Animal Protocol |
No specific animal study protocols for PERK-IN-2 are published. A typical protocol for PERK inhibitors involves using xenograft mouse models of cancer. Mice bearing A549 tumors would be randomized and treated orally with vehicle or PERK-IN-2 (e.g., 5-20 mg/kg). Tumor volume is measured every 2-3 days. At endpoint, tumors are harvested for analysis of the inhibition of p-eIF2alpha or PERK autophosphorylation via Western blot and for evaluation of the unfolded protein response (UPR) markers.
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| ADME/Pharmacokinetics |
Published pharmacokinetic data for PERK-IN-2 is currently unavailable. However, as a potent PERK inhibitor, it is predicted to have the properties necessary for oral bioavailability, including moderate molecular weight (437.42) and good membrane permeability (LogP ~3.2). It is likely cleared primarily via hepatic metabolism. DMSO solubility is > 100 mg/mL, facilitating in vivo formulations. Further studies are required to confirm its absorption, distribution, metabolism, and excretion (ADME) profile.
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| Toxicity/Toxicokinetics |
Specific toxicological data for PERK-IN-2 is not reported. However, as a research chemical targeting a critical cellular stress response pathway, it requires careful handling. Preliminary cellular assays in A549 cells do not report overt cytotoxicity at concentrations up to 0.3 microM. Systemic administration of PERK inhibitors can induce pancreatic toxicity due to the role of PERK in secretory cell health. Thus, animal studies involving in vivo administration should monitor pancreatic enzyme levels and histology to assess off-target toxicity.
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| References | |
| Additional Infomation |
PERK-IN-2 is primarily a research tool compound for studying the unfolded protein response (UPR). It has not yet entered human clinical trials for any indication. As a potent inhibitor, it is used to explore the therapeutic potential of targeting PERK in cancers where the UPR promotes cell survival, such as multiple myeloma and solid tumors. It serves as a reference standard for comparing other PERK inhibitors or for studying the pharmacological effects of PERK inhibition in preclinical models.
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| Molecular Formula |
C23H18F3N5O
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|---|---|
| Molecular Weight |
437.42
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| Exact Mass |
437.146
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| CAS # |
1337531-83-5
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| PubChem CID |
66561090
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| Appearance |
Off-white to light brown solid powder
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| LogP |
3.2
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
32
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| Complexity |
701
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| Defined Atom Stereocenter Count |
0
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| SMILES |
N1(C=C(C2C1=NC=NC=2N)C1C=C2CCN(C(=O)CC3=C(C(=CC(F)=C3)F)F)C2=CC=1)C
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| InChi Key |
JCUSVFKWUQBVHH-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H18F3N5O/c1-30-10-16(20-22(27)28-11-29-23(20)30)12-2-3-18-13(6-12)4-5-31(18)19(32)8-14-7-15(24)9-17(25)21(14)26/h2-3,6-7,9-11H,4-5,8H2,1H3,(H2,27,28,29)
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| Chemical Name |
1-[5-(4-amino-7-methylpyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindol-1-yl]-2-(2,3,5-trifluorophenyl)ethanone
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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 | 2.2861 mL | 11.4307 mL | 22.8613 mL | |
| 5 mM | 0.4572 mL | 2.2861 mL | 4.5723 mL | |
| 10 mM | 0.2286 mL | 1.1431 mL | 2.2861 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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