Lyn-IN-1 is a potent and selective dual Bcr-Abl/Lyn inhibitor with potential antineoplastic activity, it is an orally bioavailable 2-phenylaminopyrimidine derivative.
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]. Lyn-IN-1, synonyms for Bafetinib(INNO-406), is a tyrosine kinase inhibitor that against wild-type Bcr-Abl in human erythroleukemia K562 cells and human embryonic kidney 293T cells with IC50 values of 11nM and 22nM, respectively. Lyn-IN-1 also suppresses the phosphorylation of platelet-derived growth factor receptor (PDGFR) and c-Kit. In vitro, Lyn-IN-1 effectively inhibited the kinase activity of both Tyr393-phosphorylated and Tyr393-unphosphorylated forms of Abl with respective IC50 values of 72nM and 30nM, suggesting that Lyn-IN-1 had sufficiently high affinity for Bcr-Abl to enable it to bind even to an unfavourable conformation of the kinase. Lyn-IN-1 also inhibited the phosphorylation of Bcr-Abl bearing M244V, G250E, Q252H, Y253F, E255K, E255V, F317L, M351T, E355G, E359V, H396P and F486S mutations with IC50 values ranging in 81-1400nM, but it did not inhibit the phosphorylation of the T315I mutation. Lyn-IN-1 inhibited proliferation of K562 and U937 cells with IC50 values of 11nM and 10μM, respectively[3]. Lyn-IN-1 inhibited proliferation of Human mast cell (HMC)-1 with IC50 value of 51nM. Lyn-IN-1 inhibited KIT phosphorylation and inducted apoptosis in HMC-1 cells[4]. In vivo, oral administration of Lyn-IN-1 at 0.2mg/kg twice daily for 10 days significantly inhibited tumor growth, while at 20mg/kg/day completely inhibited tumor growth without adverse effects in Balb/c-nu/nu mouse bearing xenografted KU812 cells. Oral administration of Lyn-IN-1 at 200mg/kg/day significantly prolonged the survival of the Balb/c-nu/nu mice intravenously injected with BaF3/wt cells. In addition, treatment of mice bearing BaF3 cells expressing Bcr-Abl bearing M244V, G250E, Q252H, Y253F, E255K, M351T or H396P mutations with Lyn-IN-1 at a dose of 20mg/kg/day showed significant prolongation of survival without any apparent signs of toxicity[3].
作用机制
The characteristic structural features of Lyn-IN-1 are a trifl uoromethyl group on the D ring that occupies a hydrophobic pocket of the Abl ligand-binding site and an adjacent dimethylaminopyrrolidine E ring whose rotation is restricted by the trifl uoromethyl group[3].
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