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Golidocitinib (AZD-4205; JAK1-IN-3) is a novel and potent JAK1 (Janus Kinase) inhibitor with anticancer activity. It inhibits JAK1 with an IC50 of 73 nM, and exhibits little activity against JAK2 (IC50>14.7 μM) and JAK3 (IC50>30 μM). JAK1, JAK2, JAK3, and TYK2 belong to the JAK (Janus kinase) family and play critical roles in cytokine signaling. Constitutive activation of JAK/STAT pathways is associated with a wide variety of diseases such as cancer and inflammation. Golidocitinib (AZD-4205) exhibited enhanced antitumor activity in combination with an approved EGFR inhibitor, osimertinib, in a preclinical non-small-cell lung cancer (NSCLC) xenograft NCI-H1975 model.
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| ln Vitro |
Example 32: Golidocitinib is a selective inhibitor of JAK1 with an IC50 of 73 nM. It also exhibits modest inhibition of JAK2 and minimal inhibition of JAK3 (IC50, >14.7 and >30 μM, respectively). For NCI-H 1975 cells, golidocitabine (IC50 = 161 nM) substantially suppresses STAT3 phosphorylation[1].
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| ln Vivo |
In mice harboring NCI-H1975 cells, golidocitinib (12.5 mg/kg BID (twice daily), 25 m/kg BID, or 50 mg/kg BID, po) by itself increases the antitumor effects and antitumor activity of osimertinib when compared to treatment with osimertinib alone[1].
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| Additional Infomation |
Golidocitinib is an orally available inhibitor of Janus-associated kinase 1 (JAK1), with potential antineoplastic activity. Upon oral administration, golidocitinib inhibits JAK-dependent signaling and may lead to an inhibition of cellular proliferation in JAK1-overexpressing tumor cells. The JAK-STAT (signal transducer and activator of transcription) signaling pathway is a major mediator of cytokine activity and is often dysregulated in a variety of tumor cell types. Additionally, JAK1 may be a primary driver of STAT3 phosphorylation and signaling, which plays a role in neoplastic transformation, resistance to apoptosis, tumor angiogenesis, metastasis, immune evasion, and treatment resistance.
Drug Indication Treatment of peripheral T cell lymphoma |
| Molecular Formula |
C25H31N9O2
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|---|---|
| Molecular Weight |
489.572743654251
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| Exact Mass |
489.26
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| CAS # |
2091134-68-6
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| Related CAS # |
2602593-49-5;2091134-68-6;Golidocitinib HCl;
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| PubChem CID |
126715380
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
1.9
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
36
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| Complexity |
736
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| Defined Atom Stereocenter Count |
1
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| SMILES |
N(C1C=CC=C2C(C3C=CN=C(NC4=CN(C)N=C4OC)N=3)=CNC=12)C(=O)[C@H](N1CCN(C)CC1)C
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| InChi Key |
GCHDZFISOLNLRV-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H29N9O2/c1-16(34-12-10-32(2)11-13-34)23(35)28-20-7-5-6-17-18(14-27-22(17)20)19-8-9-26-25(29-19)30-21-15-33(3)31-24(21)36-4/h5-9,14-15,27H,1,10-13H2,2-4H3,(H,28,35)(H,26,29,30)
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| Chemical Name |
(2R)-N-[3-[2-[(3-Methoxy-1-methyl-pyrazol-4-yl)amino]pyrimidin-4-yl]-1H-indol-7-yl]-2-(4-methylpiperazin-1-yl)propenamide
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| Synonyms |
AZD4205 Golidocitinib AZD 4205Golidocitinibum AZD-4205
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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 (~204.26 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.11 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 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: ≥ 2.5 mg/mL (5.11 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 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: ≥ 2.5 mg/mL (5.11 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0426 mL | 10.2130 mL | 20.4261 mL | |
| 5 mM | 0.4085 mL | 2.0426 mL | 4.0852 mL | |
| 10 mM | 0.2043 mL | 1.0213 mL | 2.0426 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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