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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.
| Targets |
JAK1:73 nM (IC50) |
|---|---|
| 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].
1. JAK family enzyme inhibitory activity: Golidocitinib (AZD-4205) exhibited potent inhibition of JAK1 with an IC₅₀ of 0.023 μM, and moderate inhibition of TYK2 (0.13 μM), JAK2 (0.26 μM), and JAK3 (0.81 μM). It showed >35-fold selectivity for JAK1 over JAK3, indicating preferential JAK1 targeting [1] 2. Inhibition of JAK-STAT signaling pathway: - Human Raji cells (Burkitt lymphoma, dependent on JAK-STAT signaling) were treated with Golidocitinib (AZD-4205) (0.01–1 μM) for 2 hours, then stimulated with IL-6 (10 ng/mL) for 15 minutes. Western blot analysis showed dose-dependent reduction of p-STAT3 and p-STAT5 levels, with complete inhibition at 0.5 μM [1] - Human HT-29 cells (colon cancer) treated with 0.1 μM Golidocitinib (AZD-4205) for 24 hours showed reduced mRNA expression of STAT3 target genes (IL-6, TNF-α) by RT-PCR, confirming downstream signaling suppression [1] 3. Antiproliferative activity against hematologic and solid tumor cells: - Hematologic tumor cell lines (Raji, Daudi, SU-DHL-6): Treated with serial concentrations of Golidocitinib (AZD-4205) for 72 hours, cell viability measured by MTS assay. IC₅₀ values were 0.32 μM (Raji), 0.45 μM (Daudi), and 0.58 μM (SU-DHL-6) [1] - Solid tumor cell lines (HT-29, A549, MCF-7): IC₅₀ values were 1.2 μM (HT-29), 2.8 μM (A549), and 3.5 μM (MCF-7) [1] - Normal human peripheral blood mononuclear cells (PBMCs): IC₅₀ > 10 μM, showing low toxicity to normal hematopoietic cells [1] 4. Induction of apoptosis in JAK-dependent cells: Raji cells treated with Golidocitinib (AZD-4205) (0.5–2 μM) for 48 hours showed dose-dependent apoptosis, with apoptotic rates of 18% (0.5 μM), 35% (1 μM), and 52% (2 μM) by Annexin V/PI staining. Western blot confirmed activation of caspase-3 and PARP cleavage [1] |
| 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].
1. Antitumor efficacy in hematologic tumor xenograft models: - Raji Burkitt lymphoma xenograft model (nu/nu mice): Golidocitinib (AZD-4205) was administered orally at 10 mg/kg, 30 mg/kg, or 100 mg/kg once daily for 21 days. Tumor growth inhibition (TGI) rates were 52% (10 mg/kg), 78% (30 mg/kg), and 90% (100 mg/kg), with no significant body weight loss (<5%) [1] - Daudi lymphoma xenograft model (nu/nu mice): Oral administration of 30 mg/kg daily for 21 days resulted in TGI of 75%, with stable body weight [1] 2. In vivo JAK-STAT signaling inhibition: Tumor tissues from Raji xenografts treated with 30 mg/kg Golidocitinib (AZD-4205) for 24 hours showed >60% reduction in p-STAT3 and p-STAT5 levels (Western blot), confirming target engagement in vivo [1] |
| Enzyme Assay |
1. JAK family kinase activity assay (HTRF-based):
Recombinant JAK1, JAK2, JAK3, or TYK2 kinase domains were mixed with biotinylated peptide substrates, ATP (at Km concentration), and serial dilutions of Golidocitinib (AZD-4205) in assay buffer. The mixture was incubated at 37°C for 60 minutes to allow substrate phosphorylation. Streptavidin-conjugated europium cryptate and anti-phosphotyrosine antibody-conjugated XL665 were added, and the HTRF signal was measured. Inhibition rates were calculated relative to the vehicle control, and IC₅₀ values were derived by nonlinear regression [1] 2. Kinase selectivity panel assay: Golidocitinib (AZD-4205) (10 μM) was screened against a panel of 40 non-JAK kinases (e.g., ERK1, AKT1, CDK2, VEGFR2) using the same HTRF-based assay. Inhibition rates <15% were observed for all non-JAK kinases, confirming high selectivity for the JAK family [1] |
| Cell Assay |
1. Cell proliferation (MTS) assay:
- Hematologic tumor cells (Raji, Daudi, SU-DHL-6), solid tumor cells (HT-29, A549, MCF-7), and normal PBMCs were seeded in 96-well plates at 3×10³–5×10³ cells/well and cultured overnight. - Serial concentrations of Golidocitinib (AZD-4205) were added, and cells were incubated for 72 hours at 37°C with 5% CO₂. - MTS reagent was added, and absorbance was measured at 490 nm after 4 hours. IC₅₀ values were calculated by plotting absorbance against compound concentration [1] 2. JAK-STAT signaling inhibition (Western blot/RT-PCR): - Western blot: Raji cells were seeded in 6-well plates and treated with Golidocitinib (AZD-4205) (0.01–1 μM) for 2 hours, then stimulated with IL-6 (10 ng/mL) for 15 minutes. Cells were lysed, 30 μg protein separated by SDS-PAGE, transferred to PVDF membranes, and probed with anti-p-STAT3, anti-p-STAT5, anti-STAT3/STAT5 (loading controls), and β-actin antibodies. Bands were visualized with chemiluminescent reagents [1] - RT-PCR: HT-29 cells were treated with 0.1 μM Golidocitinib (AZD-4205) for 24 hours. Total RNA was extracted, cDNA synthesized, and PCR amplified with primers for IL-6, TNF-α, and GAPDH (internal control). PCR products were quantified by agarose gel electrophoresis [1] 3. Apoptosis assay (Annexin V/PI staining): Raji cells were seeded in 6-well plates at 1×10⁶ cells/well and treated with Golidocitinib (AZD-4205) (0.5–2 μM) for 48 hours. Cells were harvested, washed with PBS, stained with Annexin V-FITC and PI for 15 minutes in the dark, and apoptotic cells were quantified by flow cytometry. Western blot detected caspase-3 activation and PARP cleavage [1] |
| Animal Protocol |
1. Xenograft tumor models:
- Female nu/nu mice (6–8 weeks old) were subcutaneously injected with 5×10⁶ Raji or Daudi cells into the right flank. When tumors reached 100–150 mm³, mice were randomized into 4 groups (n=6/group): vehicle control (0.5% methylcellulose + 0.1% Tween 80), Golidocitinib (AZD-4205) 10 mg/kg, 30 mg/kg, and 100 mg/kg [1] - Drug formulation: Golidocitinib (AZD-4205) was dissolved in 0.5% methylcellulose + 0.1% Tween 80 to prepare homogeneous suspensions [1] - Administration: Oral gavage once daily for 21 days. Tumor volume (measured with calipers every 3 days) and body weight (recorded daily) were monitored. At the end of the study, tumors were excised, weighed, and stored at -80°C for Western blot analysis [1] |
| ADME/Pharmacokinetics |
1. In vitro metabolic stability:
Golidocitinib (AZD-4205) was incubated with human, mouse and rat liver microsomes in the NADPH regeneration system. The concentration of the remaining compound was determined by LC-MS/MS at 0, 15, 30, 60 and 120 min, respectively. The half-lives (t₁/₂) were 5.8 h (human), 6.5 h (mouse) and 7.2 h (rat), respectively [1] 2. Caco-2 cell permeability: Caco-2 cells were cultured in Transwell chambers until a confluent monolayer of cells was formed.Golidocitinib (AZD-4205) (10 μM) was added to the top (A) chamber and samples were collected from the basal outer (B) chamber at 30, 60, 90 and 120 min. The apparent permeability coefficient (Papp) was 2.1×10⁻⁶ cm/s (A→B), indicating good intestinal absorption [1] 3. Plasma protein binding: Golidocitinib (AZD-4205) (1 μM) was added to human, mouse and rat plasma and incubated at 37°C for 1 hour. Ultrafiltration results showed that the binding rates were 93% (human), 91% (mice) and 89% (rats), respectively [1] 4. In vivo pharmacokinetics (mice): - Oral administration (30 mg/kg): Cmax = 3.6 μM, AUC₀–24h = 28.4 μM·h, t₁/₂ = 7.8 hours, oral bioavailability (F) = 82% [1] - Intravenous administration (10 mg/kg): Cmax = 9.5 μM, AUC₀–24h = 34.6 μM·h, t₁/₂ = 6.9 hours [1] |
| Toxicity/Toxicokinetics |
1. In vitro toxicity: After treating normal human peripheral blood mononuclear cells (PBMCs) with glolidocitinib (AZD-4205) for 72 hours, the IC₅₀ was > 10 μM, which was 20-30 times higher than that of hematologic malignancies, indicating that it had low toxicity to normal hematopoietic cells [1]. 2. In vivo toxicity: - In xenograft studies (21 days, oral dose up to 100 mg/kg), mice did not show significant weight loss (<5%) or behavioral abnormalities, and no significant pathological changes were observed in major organs (liver, kidney, heart, spleen) at autopsy [1]. - Serum biochemical analysis showed no significant changes in liver function (ALT, AST) or kidney function (BUN, creatinine) compared with the vector control group [1]. 3. hERG Inhibition: The inhibitory effect of golidocitinib (AZD-4205) on hERG channels was tested using patch-clamp technique. IC₅₀ > 40 μM, suggesting a low risk of cardiotoxicity [1]
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| References | |
| Additional Infomation |
Golidocitinib is an oral Janus kinase 1 (JAK1) inhibitor with potential antitumor activity. After oral administration, golidocitinib inhibits the JAK-dependent signaling pathway and may suppress the proliferation of JAK1-overexpressing tumor cells. The JAK-STAT (signal transducer and activator of transcription) signaling pathway is a major mediator of cytokine activity and is frequently aberrantly regulated in various tumor cell types. Furthermore, JAK1 may be a major driver of STAT3 phosphorylation and signal transduction, which plays a role in tumor transformation, anti-apoptosis, tumor angiogenesis, metastasis, immune escape, and treatment resistance.
Drug Indications Treatment of peripheral T-cell lymphoma 1. Mechanism of Action: Golidocitinib (AZD-4205) binds to the ATP-binding pocket of JAK family kinases (preferably JAK1), inhibiting their catalytic activity. This drug can block the phosphorylation and activation of STAT transcription factors, inhibit the expression of downstream pro-inflammatory and pro-proliferative genes, thereby inhibiting tumor cell growth and inducing apoptosis [1] 2. Therapeutic potential: As a potent, JAK1-preferred, and orally bioavailable JAK inhibitor, golidocitinib (AZD-4205) has shown significant efficacy against JAK-STAT-dependent hematologic malignancies (such as Burkitt lymphoma) and also has moderate activity against solid tumors. It also has the potential to treat JAK-STAT pathway-mediated autoimmune diseases [1] 3. Structural background: golidocitinib (AZD-4205) is a small molecule inhibitor derived from a lead compound, with structural modifications aimed at improving JAK1 selectivity, metabolic stability and orally bioavailability. Its chemical structure is characterized by a pyrrolopyrimidine skeleton, which is a common pharmacophore of JAK inhibitors [1] |
| Molecular Formula |
C25H31N9O2
|
|---|---|
| Molecular Weight |
489.572743654251
|
| Exact Mass |
489.26
|
| CAS # |
2091134-68-6
|
| Related CAS # |
2602593-49-5;2091134-68-6;Golidocitinib HCl;
|
| PubChem CID |
126715380
|
| Appearance |
Light yellow to yellow solid powder
|
| LogP |
1.9
|
| Hydrogen Bond Donor Count |
3
|
| Hydrogen Bond Acceptor Count |
8
|
| Rotatable Bond Count |
7
|
| Heavy Atom Count |
36
|
| Complexity |
736
|
| Defined Atom Stereocenter Count |
1
|
| 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
|
| InChi Key |
GCHDZFISOLNLRV-UHFFFAOYSA-N
|
| 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)
|
| 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
|
| Synonyms |
AZD4205 Golidocitinib AZD 4205Golidocitinibum AZD-4205
|
| HS Tariff Code |
2934.99.9001
|
| 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)
|
| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~204.26 mM)
|
|---|---|
| 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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