The pyrido[2,3-d]pyrimidine derivative PD180970 inhibits p210(Bcr-Abl) tyrosine kinase and induces apoptosis of K562 leukemic cells

PD180970 is a novel pyrido[2,3-d]pyrimidine class of ATP-competitive inhibi tor of protein tyrosine kinases, We found that PD180970 inhibited in vivo t yrosine phosphorylation of p210(Bcr.Abl) (IC50 = 170 nM) and the p210(Bcr.A bl) substrates Gab2 and CrkL (IC50 = 80 nM) in human K562 chronic myelogeno us leukemic cells. In vitro, PD180970 potently inhibited autophosphorylatio n of p210(Bcr.Abl) (IC50 = 5 nM) and the kinase activity of purified recomb inant Abl tyrosine kinase (IC50 = 2.2 nM). Incubation of K562 cells fifth P D180970 resulted in cell death. Results of nuclear staining, apoptotic-spec ific poly(ADP-ribose) polymerase cleavage, and annexin V binding assays ind icated that PD180970 induced apoptosis of K562 cells. In contrast, PD180970 had no apparent effects on the growth and viability of p210(Bcr.Abl)-negat ive HL60 human leukemic cells, Thus, PD180970 is among the most potent inhi bitors of the p210(Bcr.Abl) tyrosine kinase, which is present in almost all cases of human chronic myelogenous leukemia, These findings indicate that PD180970 is a promising candidate as a novel therapeutic agent for Bcr-Abl- positive leukemia.