Description
A-419259 is an inhibitor of Src family kinases, including Src, LCK, Lyn, and Hck (IC
50s = 9, <3, <3, and 11.26 nM, respectively)., It is selective for these kinases over c-Abl (IC
50 = 3,000 nM) and PKC (IC
50 = >33 μM). A-419259 inhibits growth of Philadelphia chromosome-positive (Ph
+) K-562 and Meg-01 myeloid leukemia cells (IC
50s = 0.1-0.3 and 0.1 μM, respectively), but not Ph
- TF-1 and HEL cells. It induces apoptosis in K-562 cells in a concentration-dependent manner. A-419259 (300 nM) inhibits differentiation of murine embryonic stem cells while maintaining pluripotency. It reduces the total number of acute myeloid leukemia (AML) cells, as well as AML stem cells, in the bone marrow and spleen in mouse patient-derived xenograft (PDX) models of AML when administered at a dose of 30 mg/kg twice daily.
Uses
A 419259 Trihydrochloride is the hydrochloride form of A 419259 which is a Src kinase inhibitor and can be used in treatment of chronic myelogenous leukemia, lymphangioleiomyomatosis and tuberous sclerosis.
References
[1] MATTHEW B WILSON. Selective pyrrolo-pyrimidine inhibitors reveal a necessary role for Src family kinases in Bcr–Abl signal transduction and oncogenesis[J]. Oncogene, 2002, 21 53: 8075-8088. DOI:
10.1038/sj.onc.1206008[2] T PENE-DUMITRESCU. An inhibitor-resistant mutant of Hck protects CML cells against the antiproliferative and apoptotic effects of the broad-spectrum Src family kinase inhibitor A-419259[J]. Oncogene, 2008, 27 56: 7055-7069. DOI:
10.1038/onc.2008.330[3] MALCOLM A MEYN. SRC family kinase activity is required for murine embryonic stem cell growth and differentiation.[J]. Molecular Pharmacology, 2005, 68 5: 1320-1330. DOI:
10.1124/mol.104.010231[4] YORIKO SAITO. A Pyrrolo-Pyrimidine Derivative Targets Human Primary AML Stem Cells in Vivo[J]. Science Translational Medicine, 2013, 5 181. DOI:
10.1126/scitranslmed.3004387
