golidocitinib   Click here for help

GtoPdb Ligand ID: 10744

Synonyms: AZD-4205 | AZD4205 | compound 21 [PMID: 32297743] | example 32 [US9714236B2] [1] | JAK1-IN-3
Compound class: Synthetic organic
Comment: AZD4205 is a selective, orally bioavailable, ATP-competitive inhibitor of Janus kinase 1 (JAK1) that was developed by Dizal Pharmaceutical Company [2]. It has been shown to enhance antitumour activity in combination with osimertinib (an approved EGFR inhibitor) in a preclinical non-small cell lung cancer xenograft model. A higher drug concentration within the gastrointestinal tract relative to plasma in preclinical models suggests potential to treat inflammatory bowel disease. Persistently activated STAT3 has been shown to be oncogenic, and drives expression of cellular proteins which contribute to central processes in cancer progression (survival, proliferation, invasion, angiogenesis). JAK1 is the key Janus kinase responsible for cytokine-mediated STAT3 activation.
The chemical structure of AZD4205 matches that for the INN golidocitinib which was surfaced in WHO Proposed list 125 in July 2021.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 8
Hydrogen bond donors 3
Rotatable bonds 8
Topological polar surface area 116.23
Molecular weight 489.26
XLogP 1.86
No. Lipinski's rules broken 0
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Canonical SMILES COc1nn(cc1Nc1nccc(n1)c1c[nH]c2c1cccc2NC(=O)[C@H](N1CCN(CC1)C)C)C
Isomeric SMILES COc1nn(cc1Nc1nccc(n1)c1c[nH]c2c1cccc2NC(=O)[C@H](N1CCN(CC1)C)C)C
InChI InChI=1S/C25H31N9O2/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/h5-9,14-16,27H,10-13H2,1-4H3,(H,28,35)(H,26,29,30)/t16-/m1/s1
Bioactivity Comments
In a screening panel of 293 kinases 1 μM AZD4205 was highly selective. The only non-JAK family kinase inhibited by > 75% at this concentration was FLT4 [2].
Selectivity at enzymes
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Target Sp. Type Action Value Parameter Concentration range (M) Reference
Janus kinase 1 Hs Inhibitor Inhibition 7.2 pIC50 - 2
pIC50 7.2 (IC50 7x10-8 M) [2]
Description: Inhbition of JAK1 enzymatic activity.
tyrosine kinase 2 Hs Inhibitor Inhibition 5.6 pIC50 - 2
pIC50 5.6 (IC50 2.8x10-6 M) [2]
Description: Inhbition of TYK2 enzymatic activity.
Janus kinase 2 Hs Inhibitor Inhibition <4.8 pIC50 - 2
pIC50 <4.8 (IC50 >1.5x10-5 M) [2]
Description: Inhbition of JAK2 enzymatic activity.