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5.30758

Sigma-Aldrich

BMX/BTK Inhibitor II, QL47

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Synonym(s):
BMX/BTK Inhibitor II, QL47, 1-(1-Acryloylindolin-6-yl)-9-(1-methyl-1H-pyrazol-4-yl)benzo[h][1,6]naphthyridin-2(1H)-one, BMX Inhibitor II, TEC Inhibitor II, Brutonʹs Tyrosine Kinase Inhibitor V, PI 3-K Inhibitor XXI, BTK Inhibitor V, BLK Inhibitor II
Empirical Formula (Hill Notation):
C27H21N5O2
CAS Number:
Molecular Weight:
447.49

assay

≥98% (HPLC)

Quality Level

form

powder

manufacturer/tradename

Calbiochem®

storage condition

OK to freeze

color

yellow

solubility

glacial acetic acid: 2 mg/mL

storage temp.

−20°C

InChI

1S/C27H21N5O2/c1-3-25(33)31-11-10-17-4-7-21(13-24(17)31)32-26(34)9-6-19-14-28-23-8-5-18(12-22(23)27(19)32)20-15-29-30(2)16-20/h3-9,12-16H,1,10-11H2,2H3

InChI key

RTRNJQOBEOISFQ-UHFFFAOYSA-N

General description

A cell-permeable tricyclic quinoline-acrylamide analog of BMX-IN-1 (>Cat. No. 505021) that covalently modifies Cys481 in the kinase hinge region of Bruton′s tyrosine kinase (BTK) and acts as a highly potent, selective, irreversible, and time-dependent inhibitor (IC50 = 6.6 nM). Also, inhibits the activity of bone marrow kinase on chromosome X (BMX) with equal potency (IC50 = 6.7 nM). Shown to be about 300-fold less potent against Cys496Ser mutated BTK. Displays excellent selectivity against a panel of 456 protein kinases, including JAK3, BLK, TEC, ITK, and EGFR and does not affect PI 3-K/mTOR and Raf/MEK/ERK signaling pathways. Diminishes autophosphorylation of BTK on Tyr223 in cells (EC50 = 475 nM) and promotes proteasome-mediated degradation of BTK (EC50 ~ 1 M in HEK293T cells). Shown to induce cell cycle arrest at G1 phase and induce apoptotic cell death in Ramos cells. Also blocks the proliferation of several B-cell lymphoma cell lines (GI50 = 370, 200, 260,120, and 120 nM for Ramos, U2932, MM1S, RPMI8226, and BCWM.1, respectively).

Please note that the molecular weight for this compound is batch-specific due to variable water content.
A cell-permeable, BMX-IN-1 (Cat. No. 505021) family of acrylamide-containing tricyclic quinoline that acts as a dual BMX & BTK inhibitor (IC50 = 6.7 & 6.6 nM, respectively) by targeting ATP-binding site and covalently modifying kinase hinge cysteine (Cys481 in human BTK) with its eletrophilic acrylamide, while inhibiting TEC, BLK, PI 3-K kinase activity only at higher concentrations (IC50 = 195, 366, and 696 nM, respectively) and exhibiting much reduced or no potency against 29 other kinases (IC50 ≥ 1.2 µM). Likewise, potent inhibition is only seen with BTK in an affinity-based selectivity profiling among a panel of 456 kinases. Shown to effectively inhibit anti-IgM-stimulated BTK Y223 autophosphorylation and downstream effector PLCγ2 Y759 phosphorylation (IC50 = 475 & 318 nM, respectively) without affecting the phosphorylation of upstream kinase Syk, nor S6K and Erk from the PI 3-K/mTOR and Raf/Mek/Erk signaling pathway, respectively. More effective than PCI-32765 (ibrutinib) in inducing PARP & Caspase-3 cleavage in Ramos cultures (Effective conc. <5 µM vs. >10 µM; 8 h) and is more potent than AVL-292, BMX-IN-1, CGI-1746, PCI-32765 in antiproliferation activity against 8 B-cell cancer cell lines (GI50 ranges from 120 to 490 nM; 4.9- and 10.8-fold of BMX-IN-1 potency in Ramos and U2932 cultures, respectively). In addition to loss of kinase activity, irreversible inhibitor-modified BTK via Cys481 covalent bond formation is reported to exhibit shortened cellular half-life. Due to poor microsomal stability, QL47 is not recommended for in vivo studies.

Biochem/physiol Actions

Cell permeable: yes
Primary Target
BMX & BTK
Reversible: no

Packaging

Packaged under inert gas

Warning

Toxicity: Standard Handling (A)

Reconstitution

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 6 months at -20°C.

Other Notes

Wu, H., et al. 2014. ACS Chem. Biol.9, 1068.

Legal Information

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany

Storage Class

11 - Combustible Solids

wgk_germany

WGK 3

flash_point_f

Not applicable

flash_point_c

Not applicable


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