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.

Physicochemical Properties

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)

Biological Activity

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].
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].
References	[1]. Compounds and methods for inhibiting jak. WO2017050938A1.
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

Solubility Data

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. 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. 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 corn oil and mix evenly.  (Please use freshly prepared in vivo formulations for optimal results.)

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.