Sigma-Aldrich Bmx/Btk Inhibitor Ii Ql47

Assay

≥98% (HPLC)

Quality Level

100

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 (GI₅₀ranges 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 forin vivostudies.

Biochem/Physiol Actions

Cell permeable: yesPrimary Target
BMX & BTKReversible: 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.CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany