Commercial development of Src kinase inhibitors for oncology

DESCRIPTION (provided by applicant): Inhibition of tyrosine kinase activity has been identified as an approach to develop new anti-cancer drugs. Several drugs that target tyrosine kinases are now marketed in the United States and many more kinase directed drugs are in clinical trials for cancer. Directing anti-cancer therapies at discrete molecular targets that are more important for the growth or survival of cancer cells than normal cells, such as particular protein kinases, offers the potential to develop effective drugs with far less severe side effects than are observed with most current anti-cancer drugs. A proprietary, modular, structure-based drug design approach has been used to construct a library of small molecules that bind to the peptide-binding site on pp60c-src (Src), a tyrosine kinase that affects multiple pathways involved in tumorigenesis. An initial 269 compound library was screened for growth inhibition in KM12 colon and H460 lung cancer cell lines and more than 90 active compounds were identified that comprise several diverse structural classes. Compounds with nanomolar in vitro potency for inhibiting the growth of these cancer cells were selected for further development. Preliminary efficacy in mouse xenograft models has been demonstrated. Structure-activity relationship studies have provided data that were used to generate two successive probe libraries. These analogs have improved solubility and in several cases improved potency, in cells. The goal of the studies proposed in this application is to select a compound for full pre-clinical development, following the evaluation of pharmacokinetic properties and in vivo efficacy. The studies proposed in this application are relevant to public health because we propose to develop a new class of anti-cancer drugs that have the potential to be very effective in stopping cancer growth as well as preventing the spread of cancer to other organs. Because of the nature of these drugs, we expect them to be much less toxic than drugs that are currently available to cancer patients. Cancer represents a large unmet medical need in the United States and research such as that proposed in this application addresses this need.