Bcr-Abl fusion tyrosine kinase is formed because of a reciprocal chromosomal translocation between chromosomes 9 and 22, producing the Philadelphia chromosome. Bcr-Abl is expressed in chronic myeloid leukemia (CML) and a chronic of acute lymphocytic leukemia[2]. Asciminib is an allosteric inhibitor of the tyrosine kinase activity of Bcr-Abl with IC50 value of 0.5 nM. In vitro, Asciminib inhibited the proliferation of Luc-Ba/F3 cells transformed to express of Bcr-Abl WT and Bcr-Abl T315I with IC50 values of 1.0 nM and 25 nM, respectively[3]. Asciminib was selectively active against Bcr-Abl lines with IC50 values ranging in 1-20 nM, irrespective of the presence of either the p210 or the p190 Bcr-Abl isoformWylie A, Schoepfer J, Jahnke W, et al. The allosteric inhibitor ABL001 enables dual targeting of BCR–ABL1|Nature, 2017, 543(7647): 733-737|https://www.ncbi.nlm.nih.gov/pubmed/28329763. In vivo, single doses of 7.5, 15 and 30 mg/kg Asciminib, administered to mice bearing KCL-22 xenografts, inhibited pSTAT5 (Tyr694), which returned to baseline at 10, 12 and 16–20h after administration of the dose, respectivelyWylie A, Schoepfer J, Jahnke W, et al. The allosteric inhibitor ABL001 enables dual targeting of BCR–ABL1|Nature, 2017, 543(7647): 733-737|https://www.ncbi.nlm.nih.gov/pubmed/28329763. Oral administration of 3 mg/kg once daily with Asciminib for 7 days afforded 68-70% tumor growth inhibition, and oral administration of 3 mg/kg twice daily showed tumor regression in KCL-22 mouse xenograft model[3].
搜索
