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Asciminib (ABL001) is a potent and selective allosteric Bcr-Abl inhibitor; inhibits Ba/F3 cells grown with an IC50 of 0.25 nM.

Asciminib binds to the myristoyl pocket of ABL1 and induces the formation of an inactive kinase conformation. NMR and biophysical studies confirm that asciminib binds potently (dissociation constant=0.5-0.8nM) and selectively to the myristoyl pocket of ABL1 and induces the inactive C-terminal helix conformation. Asciminib binding mimics the structural consequences of myristate binding to the N terminus of ABL1. Consistent with this binding site, asciminib exhibits the same non-ATP-competitive biochemical kinetics as the BCR-ABL inhibitor GNF-2 but with approximately 100-fold greater potency. Asciminib lacks activity against more than 60 kinases, including SRC, and is similarly inactive against G-protein-coupled receptors, ion channels, nuclear receptors and transporters. In BCR-ABL1-transformed Ba/F3 cells grown without IL-3, asciminib has an anti-proliferative with IC50 value of 0.25nM. In the CML blast-phase cell line KCL-22, asciminib inhibits phosphorylation of both STAT5 (Tyr694; pSTAT5) and BCR-ABL1 (Tyr245; pBCR-ABL1) after 1h using concentrations that correlate with those required for inhibition of cell proliferation. Asciminib is selectively active against all BCR-ABL1 lines (IC50 value of 1-20nM), irrespective of the presence of either the p210 or the p190 BCR-ABL1 isoform.[1].

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