AZ2   Click here for help

GtoPdb Ligand ID: 10233

PDB Ligand Immunopharmacology Ligand
Compound class: Synthetic organic
Comment: AZ2 is a highly selective inhibitor of the lipid kinase PI3Kγ [1]. It represents a novel chemotype that binds to a conserved part of the ATP-binding pocket (Type I inhibitor-like), but once bound the inhibitor induces a DFG-out (active state) conformational change and rearrangement of the activation loop (analogous to Type II protein kinase inhibitors). This mechanism occurs only in PI3Kγ. Analogues of this novel class of PI3Kγ inhibitors, with enhanced pharmacokinetic properties and in vivo potency (e.g. Compound 15 [PMID: 29852070]), have been reported [2].
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 5
Hydrogen bond donors 1
Rotatable bonds 5
Topological polar surface area 90.54
Molecular weight 369.15
XLogP 2.83
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
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Canonical SMILES CC(=O)Nc1sc(c(n1)C)c1cc(C)c2c(c1)CN(C2=O)C(C1CC1)C
Isomeric SMILES CC(=O)Nc1sc(c(n1)C)c1cc(C)c2c(c1)CN(C2=O)[C@H](C1CC1)C
InChI InChI=1S/C20H23N3O2S/c1-10-7-15(18-11(2)21-20(26-18)22-13(4)24)8-16-9-23(19(25)17(10)16)12(3)14-5-6-14/h7-8,12,14H,5-6,9H2,1-4H3,(H,21,22,24)/t12-/m0/s1
InChI Key CNCRCDLWUGCPSJ-LBPRGKRZSA-N
Bioactivity Comments
Isoform selectivity of AZ2 has been confirmed in cellular assays (mast cells and tumour cell lines with a constitutively activated PI3K/Akt pathway) [1].
Selectivity at enzymes
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Target Sp. Type Action Value Parameter Concentration range (M) Reference
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma Primary target of this compound Hs Inhibitor Inhibition 8.6 pKd - 1
pKd 8.6 (Kd 2.24x10-9 M) [1]
Description: Binding affinity determined by SPR using a two-step binding model.
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta Hs Inhibitor Inhibition 6.7 pKi - 1
pKi 6.7 (Ki 1.99x10-7 M) [1]
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma Primary target of this compound Hs Inhibitor Inhibition 9.5 pIC50 - 1
pIC50 9.5 (IC50 3.5x10-10 M) [1]
Description: Biochemical assay using purified protein expressed from a construct containing C-terminal 6-His-tagged human p110&gamma (S144-A1102).
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha Hs Inhibitor Inhibition 5.4 pIC50 - 1
pIC50 5.4 (IC50 3.981x10-6 M) [1]
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta Hs Inhibitor Inhibition 4.5 pIC50 - 1
pIC50 4.5 (IC50 3.162x10-5 M) [1]