Discovery of a novel abl tyrosine kinase inhibitor that selectively induces apoptosis of bcr-abl-positive leukemic cells

PD180970 is a novel pyrido[2,3-d]pyrimidine class of protein tyrosine kinase inhibitor. We found that PD180970 inhibited in vivo tyrosine phosphorylation of p210Bcr-Abl and its substrates in human K562 chronic myelogenous leukemic cells at nanomolar concentrations. In vitro, PD180970 inhibited Abl tyrosine kinase activity with an IC50 = 2 nM. Incubation of K562 and other Bcr-Abl-positive cells with PD180970 led to cell death, whereas no apparent effects of PD180970 on cell growth and viability of the Bcr-Abl-negative HL60 leukemic cells were observed. While partially inhibiting proliferation of the interleukin-3-dependent normal myeloid 32D cells, PD180970 had little effect on viability of these cells. Nuclear staining, poly(ADP-ribose) polymerase cleavage, and annexin V binding assays indicated that PD180970 induced apoptosis of K562 cells. Thus, PD180970 is the most potent inhibitor of the Abl tyrosine kinase identified and selectively induces apoptosis of Bcr-Abl-positive leukemic cells. These findings indicate that PD180970 is a promising candidate as a novel therapeutic agent for the Bcr-Abl-positive human chronic myelogenous leukemia and acute lymphoblastic leukemia.