LANRAPLENIB

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Search structure


Synonyms	GS-SYK Lanraplenib
Status
Molecule Category	Free-form
UNII	A6U64OU57E


Active Pharmaceutical Ingredients Bioactive chemicals	Exact Similarity SubStructure	Threshold (%) >= 70

Structure


InChI Key	XCIGZBVOUQVIPI-UHFFFAOYSA-N
Smiles	Nc1cncc(-c2cn3ccnc3c(Nc3ccc(N4CCN(C5COC5)CC4)cc3)n2)n1
InChI	InChI=1S/C23H25N9O/c24-21-12-25-11-19(28-21)20-13-32-6-5-26-23(32)22(29-20)27-16-1-3-17(4-2-16)30-7-9-31(10-8-30)18-14-33-15-18/h1-6,11-13,18H,7-10,14-15H2,(H2,24,28)(H,27,29)

Physicochemical Descriptors

Property Name	Value
Molecular Formula	C23H25N9O
Molecular Weight	443.52
AlogP	2.03
Hydrogen Bond Acceptor	10.0
Hydrogen Bond Donor	2.0
Number of Rotational Bond	5.0
Polar Surface Area	109.73
Molecular species	NEUTRAL
Aromatic Rings	4.0
Heavy Atoms	33.0

Bioactivity

Mechanism of Action	Action	Reference
Tyrosine-protein kinase SYK inhibitor	INHIBITOR	Other PubMed


Protein: Tyrosine-protein kinase SYK Description: Tyrosine-protein kinase SYK Organism : Homo sapiens P43405 ENSG00000165025

Targets	EC50(nM)	IC50(nM)	Kd(nM)	Ki(nM)	Inhibition(%)
Enzyme Kinase Protein Kinase TK protein kinase group Tyrosine protein kinase JakA family	-	120	-	-	-
Enzyme Kinase Protein Kinase TK protein kinase group Tyrosine protein kinase JakB family	-	120	-	-	-
Enzyme Kinase Protein Kinase TK protein kinase group Tyrosine protein kinase Syk family	24-1305	6	-	-	-

Assay Description	Organism	Bioactivity	Reference
High Throughput Syk Biochemical Assay: Syk activity was measured using KinEASE (Cisbio), a time-resolved fluorescence resonance energy transfer (TR-FRET) immunoassay. In this assay, Syk-catalyzes the phosphorylation of a XL665-labeled peptide substrate. Europium conjugated phospho-tyrosine specific antibody binds the resulting phosphorylated peptide. Formation of phosphorylated peptide is quantified by TR-FRET with Europium as the donor and XL665 the acceptor in a 2-step endpoint assay. In brief, test compounds serially diluted in DMSO were delivered into Corning white, low volume, non-binding 384 well plates using the Echo 550 acoustic liquid dispenser (Labcyte®). Syk enzyme and substrates were dispensed into assay plates using a Multi-Flo (Bio-Tek Instruments). The standard 5 μL reaction mixture contained 20 μM ATP, 1 μM biotinylated peptide, 0.015 nM of Syk in reaction buffer (50 mM Hepes, pH 7.0, 0.02% NaN3, 0.1% BSA, 0.1 mM Orthovanadate, 5 mM MgCl2, 1 mM DTT, 0.025% NP-40). After 30 minutes of incubati	None	80.0 nM
High Throughput Syk Biochemical Assay: Syk activity was measured using KinEASE (Cisbio), a time-resolved fluorescence resonance energy transfer (TR-FRET) immunoassay. In this assay, Syk-catalyzes the phosphorylation of a XL665-labeled peptide substrate. Europium conjugated phospho-tyrosine specific antibody binds the resulting phosphorylated peptide. Formation of phosphorylated peptide is quantified by TR-FRET with Europium as the donor and XL665 the acceptor in a 2-step endpoint assay. In brief, test compounds serially diluted in DMSO were delivered into Corning white, low volume, non-binding 384 well plates using the Echo 550 acoustic liquid dispenser (Labcyte®). Syk enzyme and substrates were dispensed into assay plates using a Multi-Flo (Bio-Tek Instruments). The standard 5 μL reaction mixture contained 20 μM ATP, 1 μM biotinylated peptide, 0.015 nM of Syk in reaction buffer (50 mM Hepes, pH 7.0, 0.02% NaN3, 0.1% BSA, 0.1 mM Orthovanadate, 5 mM MgCl2, 1 mM DTT, 0.025% NP-40). After 30 minutes of incubati	Homo sapiens	13.5 nM
Inhibition of SYK (unknown origin) using XL665-labeled peptide as substrate in presence of ATP measured after 30 mins by TR-FRET assay	Homo sapiens	6.2 nM
Inhibition of SYK in human Ramos cells assessed as reduction in antihuman IgM F(ab)2-induced phosphorylation of BLNK at Y96 residue preincubated for 1 hr followed by antihuman IgM F(ab)2 stimulation for 5 mins by MSD high bind plate assay	Homo sapiens	24.0 nM
Inhibition of SYK in human whole blood assessed as reduction in anti-FCepsilonR1 mAb-induced basophil activation by measuring decrease in CD63 surface expression incubated for 60 mins followed by anti-FCepsilonR1 mAb stimulation for 20 mins by flow cytometry analysis	Homo sapiens	73.0 nM
Inhibition of wild-type human partial length JAK2 JH1 catalytic domain (A829 to G1132 residues) expressed in mammalian expression system by Kinomescan method	Homo sapiens	120.0 nM
Inhibition of SYK (unknown origin) in B cells assessed as reduction in alpha IgM-stimulated BTK phosphorylation at Y223 residue	Homo sapiens	26.0 nM
Inhibition of SYK (unknown origin) in B cells assessed as reduction in alpha IgM-stimulated AKT phosphorylation at S473 residue	Homo sapiens	34.0 nM
Inhibition of SYK (unknown origin) in B cells assessed as reduction in alpha IgM-stimulated ERK phosphorylation at T202/Y204 residue	Homo sapiens	37.0 nM
Inhibition of SYK (unknown origin) in B cells assessed as reduction in alpha IgM-stimulated MEK phosphorylation at S217/S221 residue	Homo sapiens	51.0 nM
Inhibition of SYK (unknown origin) in B cells assessed as reduction in alpha IgM-stimulated B cells activation by measuring reduction in CD69 expression	Homo sapiens	112.0 nM
Inhibition of SYK (unknown origin) in B cells assessed as reduction in alpha IgM-stimulated B cells activation by measuring reduction in CD86 expression	Homo sapiens	164.0 nM
Inhibition of SYK-mediated alpha IgM/alpha CD40-stimulated human B lymphocytes proliferation pretreated for 1 hr followed by stimulation with alpha IgM/alpha CD40 for 90 hrs by EdU incorporation assay	Homo sapiens	108.0 nM
Inhibition of SYK (unknown origin) in macrophages assessed as reduction in immune complex-stimulated TNFalpha secretion	Homo sapiens	180.0 nM
Inhibition of SYK (unknown origin) in macrophages assessed as reduction in immune complex-stimulated IL-1 beta secretion	Homo sapiens	90.0 nM
Inhibition of SYK (unknown origin) in macrophages assessed as reduction in immune complex-stimulated IL-6 secretion	Homo sapiens	700.0 nM

Cross References

Resources	Reference
ChEMBL	CHEMBL3986824
DrugBank	DB14770
FDA SRS	A6U64OU57E
Guide to Pharmacology	9764
PDB	R6D
PubChem	118161062
SureChEMBL	SCHEMBL16820581

CONTENTS

PREMIER has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 875508. The JU receives support from the EU’s Horizon 2020 research and innovation programme and the European Federation of Pharmaceutical Industries and Associations (EFPIA). The views reflect only the authors’ perspective and the JU is not responsible for any use that may be made of the information this manuscript contains.

Elements of the website have been developed under projects PREMIER and the Biocenter Finland Drug Discovery and Chemical Biology network. CSC-IT is thanked for providing computational resources. Content of the website is provided without guarantee for correctness. Data has been collected and integrated from multiple public sources, for the largest: FDA, HUGO Gene Nomenclature Committee, ChEMBL, IUPHAR/BPS guide to pharmacology, Reactome, UniProt, and Ensembl. Credit is given to Ensembl for collecting species images (provided under public domain licences such as Wikimedia and NHGRI).