6-(2,6-Dichloro-phenyl)-2-(4-fluoro-3-methyl-phenylamino)-8-methyl-8H-pyrido[2,3-d]pyrimidin-7-one

Uses

PD 180970 is an ATP-competitive inhibitor of p210 tyrosine kinase which selectively induces apoptosis in chronic myeloid leukemia (CML) K562 cells.

Biological Activity

PD-180970 is a potent inhibitor of the p210 Bcr-Abl tyrosine kinase.

Enzyme inhibitor

This pyridopyrimidine (FWfree-base = 429.28 g/mol) inhibits Bcr-Abl proteintyrosine kinase and induces apoptosis of K562 leukemic cells. In vitro, PD180970 potently inhibited p210Bcr-Abl autophosphorylation (IC50 = 5 nM) as well as the kinase activity of purified Abl tyrosine kinase (IC50 = 2.2 nM). Incubation of K562 cells with PD180970 resulted in cell death, with results of nuclear staining, apoptotic-specific poly(ADP-ribose) polymerase cleavage, and annexin V binding assays confirming as much. Significantly, PD180970 is without effect on the growth and viability of p210Bcr-Ablnegative HL60 human leukemic cells. Such findings demonstrate that PD180970 is among the most potent known inhibitors of the p210Bcr-Abl tyrosine kinase and that it is a promising candidate as a novel therapeutic agent for Bcr-Abl-positive leukemia

in vivo

IC 50

Bcr-Abl: 5 nM (IC₅₀, p210^Bcr-Abl kinase); Src: 0.8 nM (IC₅₀); KIT: 50 nM (IC₅₀)