An allosteric inhibitor of Abl1
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)
Cell experiment: | Ba/F3 cells are treated with a range concentration of asciminib (0-10000 nM) for 48 h. Cell proliferation is measured using the Britelite luciferase detection assay[1]. |
Animal experiment: | Mice: Asciminib efficacy in three patient-derived ALL systemic xenograft models (ALL-7015, AL-7119 and AL-7155) is assessed by FACS monitoring of the percentage of CD45+ cells per live cell in blood samples taken at varying time points after dosing with either 7.5 mg/kg BID (group 2) or 30 mg/kg BID (group 3) asciminib for 3 weeks[1]. |
参考文献: [1]. Wylie AA, et al. The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1. Nature. 2017 Mar 30;543(7647):733-737. | |
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