ZANUBRUTINIB

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Synonyms
Status
Molecule Category UNKNOWN
UNII AG9MHG098Z

Structure

InChI Key RNOAOAWBMHREKO-QFIPXVFZSA-N
Smiles C=CC(=O)N1CCC([C@@H]2CCNc3c(C(N)=O)c(-c4ccc(Oc5ccccc5)cc4)nn32)CC1
InChI
InChI=1S/C27H29N5O3/c1-2-23(33)31-16-13-18(14-17-31)22-12-15-29-27-24(26(28)34)25(30-32(22)27)19-8-10-21(11-9-19)35-20-6-4-3-5-7-20/h2-11,18,22,29H,1,12-17H2,(H2,28,34)/t22-/m0/s1

Physicochemical Descriptors

Property Name Value
Molecular Formula C27H29N5O3
Molecular Weight 471.56
AlogP 4.22
Hydrogen Bond Acceptor 6.0
Hydrogen Bond Donor 2.0
Number of Rotational Bond 6.0
Polar Surface Area 102.48
Molecular species NEUTRAL
Aromatic Rings 3.0
Heavy Atoms 35.0

Bioactivity

Mechanism of Action Action Reference
Tyrosine-protein kinase BTK inhibitor INHIBITOR FDA
Protein: Tyrosine-protein kinase BTK
Description: Tyrosine-protein kinase BTK
Organism : Homo sapiens
Q06187 ENSG00000010671
Targets EC50(nM) IC50(nM) Kd(nM) Ki(nM) Inhibition(%)
Adhesion
- 510 - - -
Enzyme Cytochrome P450 Cytochrome P450 family 2 Cytochrome P450 family 2C Cytochrome P450 2C19
- 7600 - - -
Enzyme Cytochrome P450 Cytochrome P450 family 2 Cytochrome P450 family 2C Cytochrome P450 2C8
- 4000 - - -
Enzyme Cytochrome P450 Cytochrome P450 family 2 Cytochrome P450 family 2C Cytochrome P450 2C9
- 5700 - - -
Enzyme Cytochrome P450 Cytochrome P450 family 3 Cytochrome P450 family 3A Cytochrome P450 3A4
- 14300-60600 - - -
Enzyme Kinase Protein Kinase TK protein kinase group Tyrosine protein kinase EGFR family
- 3-606 - - -
Enzyme Kinase Protein Kinase TK protein kinase group Tyrosine protein kinase JakA family
- 580 - - -
Enzyme Kinase Protein Kinase TK protein kinase group Tyrosine protein kinase JakB family
- 580 - - -
Enzyme Kinase Protein Kinase TK protein kinase group Tyrosine protein kinase Src family
- 1 - - 29
Enzyme Kinase Protein Kinase TK protein kinase group Tyrosine protein kinase Tec family
- 0-2 - - -
Membrane receptor
- 510 - - -
Assay Description Organism Bioactivity Reference
Time-Resolved Fluorescence Resonance Energy Transfer Assay: Compounds disclosed herein were tested for inhibition of Btk kinase activity in an assay based on time-resolved fluorescence resonance energy transfer methodology. Recombinant Btk was pre-incubated with the compounds disclosed herein at room temperature for 1 hour in an assay buffer containing 50 mM Tris pH7.4, 10 mM MgCl2, 2 mM MnCl2, 0.1 mM EDTA, 1 mM DT, 20 nM SEB, 0.1% BSA, 0.005% tween-20. The reactions were initiated by the addition of ATP (at the concentration of ATP Km) and peptide substrate (Biotin-AVLESEEELYSSARQ-NH2). After incubating at room temperature for 1 h, an equal volume of stop solution containing 50 mM HEPES pH7.0, 800 mM KF, 20 mM EDTA, 0.1% BSA, Eu cryptate-conjugated p-Tyr66 antibody and streptavidin-labeled XL665 was added to stop the reaction. Plates were further incubated at room temperature for 1 hour, and then the TR-FRET signals (ex337 nm, em 620 nm/665 nm) were read on BMG PHERAstar FS instrument. The residual enzyme activity in presence of increasing concentrations of compounds was calculated based on the ratio of fluorescence at 615 nm to that at 665 nm. The IC50 for each compound was derived from fitting the data to the four-parameter logistic equation by Graphpad Prism software. Homo sapiens 2.0 nM
Inhibition of JAK3 (unknown origin) preincubated for 1 hr followed by Biotin-AVLESEEELYSSARQ-NH2 substrate addition in presence of ATP and measured after 1 hr by TR-FRET assay Homo sapiens 580.0 nM
Inhibition of BTK in human Ramos cells assessed as reduction in BTK phosphorylation at Tyr223 residue preincubated for 1 hr followed by pervanadate or Na3VO4 stimulation for 20 mins by HTRF assay Homo sapiens 1.8 nM
Inhibition of N-terminal His-tagged recombinant human BTK (393 to 659 residues) expressed in baculovirus infected Sf9 cells preincubated for 1 hr followed by Biotin-AVLESEEELYSSARQ-NH2 substrate addition in presence of ATP and measured after 1 hr by TR-FRET assay Homo sapiens 0.3 nM
Inhibition of EGFR (unknown origin) preincubated for 1 hr followed by Biotin-AVLESEEELYSSARQ-NH2 substrate addition in presence of ATP and measured after 1 hr by TR-FRET assay Homo sapiens 2.6 nM
Antiproliferative activity against human Rec1 cells after 6 days by Celltiter-glo luminescent cell viability assay Homo sapiens 0.36 nM
Antiproliferative activity against human OCI-LY10 cells after 6 days by Celltiter-glo luminescent cell viability assay Homo sapiens 0.35 nM
Inhibition of human BTK using poly[Glu:Tyr] (4:1) as substrate preincubated for 60 mins followed by [gamma-33P]-ATP addition and measured after 120 mins by filter binding method Homo sapiens 0.92 nM
Inhibition of ITK (unknown origin) preincubated for 1 hr followed by Biotin-AVLESEEELYSSARQ-NH2 substrate addition in presence of ATP and measured after 1 hr by TR-FRET assay Homo sapiens 56.0 nM
Inhibition of TEC (unknown origin) preincubated for 1 hr followed by Biotin-AVLESEEELYSSARQ-NH2 substrate addition in presence of ATP and measured after 1 hr by TR-FRET assay Homo sapiens 2.0 nM
Inhibition of HER2 (unknown origin) preincubated for 1 hr followed by Biotin-AVLESEEELYSSARQ-NH2 substrate addition in presence of ATP and measured after 1 hr by TR-FRET assay Homo sapiens 530.0 nM
Inhibition of human BLK using poly[Glu:Tyr] (4:1) as substrate preincubated for 60 mins followed by [gamma-33P]-ATP addition and measured after 120 mins by filter binding method Homo sapiens 1.13 nM
Inhibition of human BMX using poly[Glu:Tyr] (4:1) as substrate preincubated for 60 mins followed by [gamma-33P]-ATP addition and measured after 120 mins by filter binding method Homo sapiens 0.62 nM
Inhibition of human BRK using poly[Glu:Tyr] (4:1) as substrate preincubated for 60 mins followed by [gamma-33P]-ATP addition and measured after 120 mins by filter binding method Homo sapiens 33.0 nM
Inhibition of human HER4 using poly[Glu:Tyr] (4:1) as substrate preincubated for 60 mins followed by [gamma-33P]-ATP addition and measured after 120 mins by filter binding method Homo sapiens 1.58 nM
Inhibition of human FGR using poly[Glu:Tyr] (4:1) as substrate preincubated for 60 mins followed by [gamma-33P]-ATP addition and measured after 120 mins by filter binding method Homo sapiens 155.0 nM
Inhibition of human FRK using poly[Glu:Tyr] (4:1) as substrate preincubated for 60 mins followed by [gamma-33P]-ATP addition and measured after 120 mins by filter binding method Homo sapiens 379.0 nM
Inhibition of human LCK using poly[Glu:Tyr] (4:1) as substrate preincubated for 60 mins followed by [gamma-33P]-ATP addition and measured after 120 mins by filter binding method Homo sapiens 187.0 nM
Inhibition of human TXK using poly[Glu:Tyr] (4:1) as substrate preincubated for 60 mins followed by [gamma-33P]-ATP addition and measured after 120 mins by filter binding method Homo sapiens 2.95 nM
Inhibition of EGFR in human A431 cells assessed as reduction in EGFR phosphorylation at Tyr1068 residues preincubated for 1 hr followed by human EGF stimulation and measured after 10 mins by HTRF assay Homo sapiens 606.0 nM
Inhibition of TEC phosphorylation in HEK293 cells peincubated for 3 hrs followed by pervanadate stimulation and measured after 20 mins by MSD assay Homo sapiens 204.7 nM
Inhibition of human SRC at 1 uM using poly[Glu:Tyr] (4:1) as substrate preincubated for 15 to 20 mins followed by [gamma-33P]-ATP addition and measured after 120 mins by filter binding method relative to control Homo sapiens 29.0 %
Inhibition of human FYN at 1 uM using poly[Glu:Tyr] (4:1) as substrate preincubated for 15 to 20 mins followed by [gamma-33P]-ATP addition and measured after 120 mins by filter binding method relative to control Homo sapiens 50.0 %
Inhibition of human LYN at 1 uM using poly[Glu:Tyr] (4:1) as substrate preincubated for 15 to 20 mins followed by [gamma-33P]-ATP addition and measured after 120 mins by filter binding method relative to control Homo sapiens 35.0 %
Inhibition of human LCK at 1 uM using poly[Glu:Tyr] (4:1) as substrate preincubated for 15 to 20 mins followed by [gamma-33P]-ATP addition and measured after 120 mins by filter binding method relative to control Homo sapiens 73.0 %
Inhibition of GP6 in human whole blood assessed as protein-mediated platelet aggregation preincubated for 15 mins followed by collagen stimulation and measured for 10 mins by multiple electrode aggregometry Homo sapiens 510.0 nM
Inhibition of full-length N-terminal GST tagged BTK (2 to 659 residues) (unknown origin) expressed in Sf21 insect cells using NH2-ETVYSEVRK-biotin as substrate preincubated for 1 hr followed by ATP addition and measured after 2 hrs by ELISA Homo sapiens 2.2 nM
Inhibition of full-length N-terminal GST-tagged BMX (1 to 675 residues) (unknown origin) expressed in Sf21 insect cells using NH2-ETVYSEVRK-biotin as substrate preincubated for 1 hr followed by ATP addition and measured after 2 hrs by ELISA Homo sapiens 5.4 nM
Inhibition of full-length N-terminal GST-tagged ITK (2 to 620 residues) (unknown origin) expressed in Sf21 insect cells using NH2-ETVYSEVRK-biotin as substrate preincubated for 1 hr followed by ATP addition and measured after 2 hrs by ELISA Homo sapiens 65.9 nM
Inhibition of N-terminal DYKDDDD-tagged EGFR (669 to 1210 residues) (unknown origin) expressed in Sf21 insect cells using NH2-ETVYSEVRK-biotin as substrate preincubated for 1 hr followed by ATP addition and measured after 2 hrs by ELISA Homo sapiens 21.2 nM
Inhibition of full-length N-terminal GST tagged BTK (1 to 659 residues) (unknown origin) expressed in Sf21 insect cells using NH2-ETVYSEVRK-biotin as substrate preincubated for 1 hr followed by ATP addition and measured after 2 hrs by ELISA Homo sapiens 2.2 nM
Inhibition of N-terminal DYKDDDD-tagged EGFR (669 to 1210 residues) (unknown origin) expressed in Sf21 insect cells using NH2-ETVYSEVRK-biotin as substrate preincubated for 1 hr followed by ATP addition and measured after 2 hrs by ELISA Homo sapiens 6.0 nM
Inhibition of N-terminal GST-tagged BMX (1 to 675 residues) (unknown origin) expressed in Sf21 insect cells using NH2-ETVYSEVRK-biotin as substrate preincubated for 1 hr followed by ATP addition and measured after 2 hrs by ELISA Homo sapiens 11.5 nM
Inhibition of N-terminal GST-tagged ITK (2 to 620 residues) (unknown origin) expressed in Sf21 insect cells using NH2-ETVYSEVRK-biotin as substrate preincubated for 1 hr followed by ATP addition and measured after 2 hrs by ELISA Homo sapiens 202.9 nM
Antiproliferative activity against human TMD8 cells assessed as reduction in cell viability incubated for 72 hrs by celltiter-glo assay Homo sapiens 3.8 nM
Inhibition of human BTK using poly-Glu-Tyr (4:1) as substrate incubated for 1 hr by ELISA Homo sapiens 3.5 nM
Inhibition of GST-tagged human EGFR (668 to 1210 residues) expressed in baculovirus expression system using poly-Glu-Tyr (4:1) as substrate incubated for 1 hrs by ELISA Homo sapiens 38.3 nM

Cross References

Resources Reference
ChEMBL CHEMBL3936761
DrugBank DB15035
DrugCentral 5353
FDA SRS AG9MHG098Z
Guide to Pharmacology 9861
PubChem 135565884
SureChEMBL SCHEMBL17842597
ZINC ZINC000584641430
CONTENTS