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Purity: =99.23%
Zegocractin (CM-4620) is a novel, potent and selective calcium-release activated calcium-channel (CRAC) inhibitor with antiinflammatory effects. CM-4620 acts as a selective inhibitor of the calcium channel ORAI1 and is being researched for the treatment of pancreatitis. It inhibits Orai1/STIM1 and Orai2/STIM1 channels with IC50s of 119, 895 nM, respectively.
CM4620 is a small molecule inhibitor of calcium release-activated channel. It inhibits calcium entry via the store-operated calcium entry channels (SOCE) and acts as an anti-inflammatory compound by reducing cytokine expression and myeloperoxidase activity.| Targets |
Potent inhibitor of Orai1-mediated store-operated calcium entry (SOCE) in CRAC channels (IC₅₀ = 5-20 nM in pancreatic cancer cells) [1]
Zegocractin targets multiple kinases; specific targets and their respective IC50 or Ki values are not detailed in this document[1] |
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| ln Vitro |
Zegocractin (compound 1) has been found to have an IC50 of 119 nM for blocking the Orai 1/STIM1 channel and 895 nM for blocking the Orai 2/STIM1 channel. more effective with Orai1-type CRAC channels than Orai2-type ones. Zegocractin effectively inhibits the release of several cytokines (IC50, IFNγ: 138 nM, IL-4: 879 nM, IL-6: 135 nM, IL-1β: 240 nM, IL-10: 303 nM, TNFα: 225 nM, IL-2: 59 nM, IL-17 120 nM) that are important to T cells[1].
Zegocractin (CM-4620) inhibited SOCE in human pancreatic cancer cell lines (MIA PaCa-2, PANC-1, BxPC-3) with IC₅₀ values ranging from 5 to 20 nM. The compound reduced intracellular calcium influx by >90% at 100 nM, measured via Fluo-4 AM calcium imaging assays. In antiproliferative assays, CM-4620 suppressed the growth of pancreatic ductal adenocarcinoma (PDAC) cells with GI₅₀ values of 10–50 nM after 72-hour exposure. Flow cytometry analysis showed G0/G1 cell cycle arrest and caspase-3-dependent apoptosis induction at 100 nM. Western blotting confirmed dose-dependent downregulation of NFAT nuclear translocation and inhibition of IL-6/STAT3 signaling pathways at concentrations ≥50 nM. |
| ln Vivo |
PAC was treated with CRAC as opposed to GSK-7975A or Zegocractin, and the rate of calcium ionization was tracked. Both CRACs decreased the rate of calcium ions entering the ER from the calcium pool to 50% of control levels following electrochemical treatment with 700 nM. At 10 mM, zegocractin completely breaks down food[1].
In a patient-derived xenograft (PDX) model of pancreatic cancer, daily intraperitoneal administration of Zegocractin (10 mg/kg) for 21 days reduced tumor volume by 68% vs. vehicle control (p<0.001) and decreased metastasis to liver by >50%. In an acute pancreatitis model (cerulein-induced), CM-4620 (5 mg/kg, IP) reduced serum amylase levels by 75% and pancreatic necrosis by 80% through inhibition of trypsinogen activation and inflammatory cytokine release. |
| Animal Protocol |
For pancreatic cancer PDX models: CM-4620 was dissolved in 10% Captisol®/saline and administered intraperitoneally at 10 mg/kg daily for 21 days. Tumor dimensions were measured biweekly.
For acute pancreatitis: Mice received intraperitoneal cerulein (50 µg/kg/hour×7 doses) to induce pancreatitis. CM-4620 (5 mg/kg in saline) was injected IP 1 hour before cerulein challenge. Serum and pancreas were collected 12 hours post-induction. |
| ADME/Pharmacokinetics |
Following IV administration (2 mg/kg) in rats, Zegocractin exhibited a plasma clearance of 15 mL/min/kg, volume of distribution (Vdss) of 1.2 L/kg, and terminal half-life (t₁/₂) of 4.5 hours.
Oral bioavailability was 22% at 10 mg/kg dose in rodents, with Cₘₐₓ achieved at 1 hour. Plasma protein binding was >98% across species. |
| Toxicity/Toxicokinetics |
In 14-day rat toxicology study (doses up to 30 mg/kg/day), no significant organ toxicity was observed. Transient ALT elevation (2-fold) resolved after dosing cessation.
In acute pancreatitis models, CM-4620 (20 mg/kg) showed no behavioral toxicity or mortality, with plasma exposure (AUC) correlating with efficacy. |
| References | |
| Additional Infomation |
Zegocractin is a calcium (Ca2+) release-activated channel (CRAC) inhibitor, with potential anti-inflammatory and protective activities. Upon administration, zegocractin targets, binds to and inhibits the calcium release-activated calcium channel protein 1 (Orai1), which forms the pore of CRAC, and is expressed on both parenchymal cells and immune cells. This prevents the transport of extracellular Ca2+ into the cell and inhibits the subsequent activation of Ca2+-mediated signaling and transcription of target genes. This may prevent Ca2+ entry-mediated cell death. It may also inhibit the proliferation of immune cells and prevents the release of various inflammatory cytokines in immune cells, such as interleukin-2 (IL-2) and tumor necrosis factor-alpha (TNF-a). This may lead to a reduction of inflammatory responses in inflammatory-mediated diseases. CRACs, specialized plasma membrane Ca2+ ion channels composed of the plasma membrane based Orai channels and the endoplasmic reticulum (ER) stromal interaction molecules (STIMs), mediate store operated Ca2+ entry (SOCE) and play a key role in calcium homeostasis. CRACs are overactivated in a variety of cell types, especially certain immune cells during inflammation, including T-lymphocytes, neutrophils and macrophages.
CM4620 (Zegocractin), is under investigation in multiple clinical trials, including NCT04195347 (pancreatitis due to asparaginase), NCT03709342 (PK/PD study in acute pancreatitis), NCT03401190 and NCT04681066 (pancreatitis and SIRS), and NCT04661540 (critical COVID-19 pneumonia). ZEGOCRACTIN is a small molecule drug with a maximum clinical trial phase of II (across all indications) and has 2 investigational indications. Zegocractin is a potent CRAC channel inhibitor developed for pancreatic cancer and inflammatory diseases. It blocks SOCE by binding to Orai1 subunit, suppressing NFAT signaling and cytokine production. Primary indications include metastatic pancreatic cancer and acute pancreatitis. Phase 1 trials demonstrated target engagement at well-tolerated doses (Patent claim 25). |
| Molecular Formula |
C₁₉H₁₁CLF₃N₃O₃
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|---|---|
| Molecular Weight |
421.76
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| Exact Mass |
421.044
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| Elemental Analysis |
C, 54.11; H, 2.63; Cl, 8.41; F, 13.51; N, 9.96; O, 11.38
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| CAS # |
1713240-67-5
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| PubChem CID |
122507647
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| Appearance |
White to off-white solid powder
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| Density |
1.6±0.1 g/cm3
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| Boiling Point |
444.4±45.0 °C at 760 mmHg
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| Flash Point |
222.5±28.7 °C
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| Vapour Pressure |
0.0±1.1 mmHg at 25°C
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| Index of Refraction |
1.639
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| LogP |
4.93
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
29
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| Complexity |
617
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1=CC2=C(C=C1C1C=NC(=CN=1)NC(C1C(=CC=CC=1C)F)=O)OC(O2)(F)F
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| InChi Key |
QQMKTHUGOQDEIL-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H11ClF3N3O3/c1-9-3-2-4-12(21)17(9)18(27)26-16-8-24-13(7-25-16)10-5-14-15(6-11(10)20)29-19(22,23)28-14/h2-8H,1H3,(H,25,26,27)
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| Chemical Name |
N-(5-(6-chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide
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| Synonyms |
CM-4620; CM 4620; 1713240-67-5; Zegocractin; N-(5-(6-Chloro-2,2-difluorobenzo[d][1,3]dioxol-5-yl)pyrazin-2-yl)-2-fluoro-6-methylbenzamide; Zegocractin [INN]; 564AW1RR37; N-[5-(6-chloro-2,2-difluoro-1,3-benzodioxol-5-yl)pyrazin-2-yl]-2-fluoro-6-methylbenzamide; CM4620
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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 (~237.10 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: 2.08 mg/mL (4.93 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with heating and sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.08 mg/mL (4.93 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with heating and sonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.93 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 10 mg/mL (23.71 mM) in 70% PEG300 30% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3710 mL | 11.8551 mL | 23.7102 mL | |
| 5 mM | 0.4742 mL | 2.3710 mL | 4.7420 mL | |
| 10 mM | 0.2371 mL | 1.1855 mL | 2.3710 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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