BMX/BTK Inhibitor II, QL47

Cell permeable: yes

Primary Target
BMX & BTK

Reversible: no

Toxicity: Standard Handling (A)

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.

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

Packaged under inert gas

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

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