A 419259 is a Potent Src Inhibitor
Posted On 2020-10-08
Chronic myelogenous leukemia (CML) is a human malignancy and affects hematopoietic progenitor cells. The CML is driven by Bcr-Abl. Additionally, Bcr-Abl is a 210 kDa chimeric tyrosine kinase that transforms fibroblasts, growth factor-dependent hematopoietic cell lines.
Bcr-Abl is a constitutively active protein-tyrosine kinase and can stimulate the proliferation and survival of myeloid progenitors. A-419259 is a pan inhibitor and exerts a global inhibition of myeloid Src family kinase (SFK) activity.
In the following paragraph, we will introduce this inhibitor in vitro and in vivo.
A 419259 is an Src family kinases inhibitor with IC50s of 9 nM, 3 nM, and 3 nM for Src, Lck, and Lyn, respectively.
A 419259 is a second-generation pyrrolo-pyrimidine designed to enhance selectivity towards the Src family relative to other cytoplasmic tyrosine kinases. A-419259 inhibits K-562 cells with an IC50 between 0.1 μM and 0.3 μM. It also inhibits Meg-01 cell proliferation with an IC50 of approximately 0.1 μM. A-419259 also potently induces apoptosis in K-562 cells beginning at 0.1 μM in a dose-dependent manner.
PP2 is a reversible Src family kinases inhibitor with IC50s of 4 and 5 nM for Lck and Fyn, respectively. It inhibits Src kinase autophosphorylation in both Ph+ cell lines (K-562 and Meg-01) with an IC50 between 3 and 10 μM. While A-419259 blocks kinase activation between 0.1 and 0.3 μM.
A-419259 strongly inhibits DAGM/Bcr-Abl cell proliferation in the absence of IL-3 with an IC50 between 0.1 and 0.3 μM. As a broad-spectrum pyrrolo-pyrimidine inhibitor, it blocks proliferation and induces apoptosis in CML cell lines. A-419259 inhibits overall SFK activity in many CML cell lines with an IC50 value of 0.1-0.3 μM.
In vivo, In female CD-1 nude mice with an orthotopic injection of CAL51 cells. A-419259 treatment results in significantly-reduced tumor growth compared with vehicle controls.
In conclusion, A-419259 a promising Src kinases inhibitor and can be used for cancer research.
Pene-Dumitrescu T, et al. Oncogene (2008) 27, 7055-7069