The Ph1 chromosome arises as a result of a translocation between chromosomes 9 and 22, which fuses two genes, termed bcr and abl. The involvement of bcr-abl fusion proteins in Ph1 positive chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL) represents the best mechanism of action model in human cancer. This group has been formed to develop drugs which specifically target the bcr-abl fusion as a means of treating Ph1 positive leukemia patients. The groups strategy involves very high throughput drug screening technology, facilitated by recent advances which make it possible to rapidly evaluate hundreds of thousands of samples. Oncogene Science has developed the leading technology in this area. Our experience over the last seven years has clearly demonstrated that running several distinct screens, each capable of identifying unique leads, is the best way to generate high quality leads. Dr. Goddard's group will run two screens (one in vitro, one in vivo) which target the activated tyrosine kinase activity of the bcr-abl fusion protein and one which seeks compounds which transcriptionally inhibit expression of the fusion gene. Dr. Katz heads a group which will supply 80,000 fungal fermentation extracts to screen. Screens will also evaluate 20,000 compounds from Oncogene Science's chemical library. Leads from the screens will be prioritized on the basis of potency and selectivity and then analoged by Dr. J. Slack's SAR chemistry team. Following further analysis in a variety of hematological cell culture models by Dr. Borzillo's group, the best leads will proceed into animal models. One group, headed by Dr. J. Groffen, will test leads in a murine ALL model, while Dr. Van Etten's group will test leads in a CML-like model. We believe this NCDDG represents a powerful team for the generation of novel, mechanism of action based drug candidates for Ph1 positive leukemia.