Biochem/physiol Actions

Reversible: no

Primary TargetBMX & BTK

Cell permeable: yes

General description

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.

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.

Legal Information

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

Other Notes

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

Packaging

5 mg in Glass bottle

Packaged under inert gas

Reconstitution

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

Warning

Toxicity: Standard Handling (A)