Asciminib is an allosteric inhibitor of Abl1 (IC50 = 0.45 nM).1 It is selective for Abl1 over a panel of more than 60 additional kinases (IC50s = >10 μM), as well as ion channels, nuclear receptors, G protein-coupled receptors (GPCRs), and transporters. Asciminib inhibits the proliferation of Luc-Ba/F3 cells transformed with wild-type Bcr-Abl1 or the drug-resistant mutant Bcr-Abl1T315I (GI50s = 1 and 25 nM, respectively), as well as other drug-resistant mutants.2 It reduces tumor growth in a KCL-22 chronic myelogenous leukemia (CML) mouse xenograft model when administered at a dose of 3 mg/kg twice per day and induces tumor regression at doses of greater than or equal to 7.5 mg/kg twice per day.
1.Wylie, A.A., Schoepfer, J., Jahnke, W., et al.The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1Nature543(7647)733-737(2017) 2.Schoepfer, J., Jahnke, W., Berellini, G., et al.Discovery of asciminib (ABL001), an allosteric inhibitor of the tyrosine kinase activity of BCR-ABL1J. Med. Chem.61(18)8120-8135(2018)