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CNX-774

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CNX-774
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Cat #: V0645 CAS #: 1202759-32-7 Purity ≥ 98%

Description: CNX-774 (CNX774) is an irreversible/covalent, orally bioavailable, and highly selective inhibitor of BTK (Bruton's tyrosine kinase) with potential anticancer activity. It inhibits BTK with an IC50 of<1 nM. CNX-774 acts by forming a covalent bond with the Cys-481 residue within the active site of BTK, which is an key enzyme in the B-cell antigen receptor (BCR) signaling pathway, and also plays an pivotal role in the maturation of mast cells activation and B cells.

References: [1]. Matthew Labenski, et al. In Vitro Reactivity Assessment of Covalent Drugs Targeting Bruton's Tyrosine Kinase.

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Molecular Weight (MW)499.5
Molecular FormulaC26H22FN7O3
CAS No.1202759-32-7
Storage-20℃ for 3 years in powder formrr
-80℃ for 2 years in solvent
Solubility In VitroDMSO: 100 mg/mL (200.2 mM)rr
Water: <1 mg/mLrr
Ethanol: 2 mg/mL (4.0 mM)
SMILES CodeO=C(NC)C1=NC=CC(OC2=CC=C(NC3=NC=C(F)C(NC4=CC=CC(NC(C=C)=O)=C4)=N3)C=C2)=C1
SynonymsCNX 774; CNX-774; CNX774; Chemical Name: 4-(4-((4-((3-acrylamidophenyl)amino)-5-fluoropyrimidin-2-yl)amino)phenoxy)-N-methylpicolinamide InChi Key: VVLHQJDAUIPZFH-UHFFFAOYSA-N InChi Code: InChI=1S/C26H22FN7O3/c1-3-23(35)31-17-5-4-6-18(13-17)32-24-21(27)15-30-26(34-24)33-16-7-9-19(10-8-16)37-20-11-12-29-22(14-20)25(36)28-2/h3-15H,1H2,2H3,(H,28,36)(H,31,35)(H2,30,32,33,34)
ProtocolIn VitroIn vitro activity: CNX-774 is a potent, irreversible/covalent, orally bioactive, and highly selective BTK (Bruton’s tyrosine kinase) inhibitor with IC50 of<1 nM. It forms a ligand-directed covalent bond with Cys-481, a non-conserved amino acid within the active site of the enzyme. Kinase Assay: In biochemical assays, CNX-774 has demonstrated potent inhibition of Btk with an IC50 of<1nM in a continuous-read assay. The covalent bonding of CNX-774 to Btk was confirmed by incubating recombinant Btk protein with a 10-fold molar excess of CNX-774 for 1 hour at room temperature and analysis by MALDI-TOF MS. A shift of protein mass corresponding to the molecular weight of CNX-774 confirmed the covalent bonding of CNX-774 to Btk. Digestion of the covalently bonded Btk with pepsin followed by MSMS analysis established the bonding of CNX-774 to Cys-481. Cell Assay: In cellular assays, CNX-774 demonstrates potent inhibitory activity towards BTK with IC50 of 1-10 nM by targeting Cys-481 residue within the ATP binding site of the enzyme. Cellular potency as well as prolonged duration of action of CNX-774 was demonstrated in Ramos cells by using a biotinylated covalent probe that targets the same Cysteine residue as CNX-774. CNX-774 was found to be >90% extractable after 2 hrs of incubation in both rat and human whole blood. These results demonstrate that CNX-774 has potent inhibitory activity towards the intended target, Btk, while achieving remarkable specificity in a variety of assays designed to assess off-target reactivity towards abundant cellular thiols and blood proteins.
In VivoCNX-774 is stable and non-reactive in fresh human and rat whole blood and does not covalently bond to any of the mid-level abundance human plasma proteins. CNX-774 demonstrates potent inhibitory activity towards the intended target, Btk, while achieving remarkable specificity in a variety of assays designed to assess off-target reactivity towards abundant cellular thiols and blood proteins.
These protocols are for reference only. InvivoChem does not independently validate these methods.
Preparing Stock Solutions
Solvent volume to be added Mass (the weight of a compound)
Mother liquor concentration 1mg5mg10mg20mg
1mM2.0020 mL10.0100 mL20.0200 mL40.0400 mL
5mM0.4004 mL2.0020 mL4.0040 mL8.0080 mL
10mM0.2002 mL1.0010 mL2.0020 mL4.0040 mL
20mM0.1001 mL0.5005 mL1.0010 mL2.0020 mL
Quality Control Documentation
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%DMSO + % + %Tween 80 + %ddH2O
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Method for preparing DMSO master liquid: mg drug pre-dissolved in µL DMSO(Master liquid concentration mg/mL) ,Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
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