The invention also relates to pharmaceutical compositions containing such analogs and to methods of treating a condition in a mammal with such analogs and compositions. Provisional Application Ser. The entire disclosure of these applications are relied upon and incorporated by reference herein.
The United States government has certain rights in the invention. Many drugs administered to treat a disease are targeted against general differences between a diseased cell and a normal cell. For example, paclitaxel, which is used to treat ovarian and breast cancer and inhibits microtubule function, is thought to exhibit tumor cell specificity based on the greater rate of proliferation of tumor cells relative to normal cells Miller and Ojima, Chem.
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However, despite this consensus view, paclitaxel's in vitro activity varies widely across tumor cell lines Weinstein et al. Molecularly targeted therapeutics represent a promising new approach to anti-cancer drug discovery Shawver et al. Using this approach, small molecules are designed to inhibit directly the very oncogenic proteins that are mutated or overexpressed in specific tumor cell types. By targeting specific molecular defects found within tumor cells, this approach may ultimately yield therapies tailored to each tumor's genetic makeup.
Two recent examples of successful molecularly targeted anti-cancer therapeutics are Gleevec imatinib mesylate , an inhibitor of the breakpoint cluster region-abelsen kinase BCR-ABL oncoprotein found in Philadelphia chromosome-positive chronic myelogenous leukemia Capdeville et al. A complementary strategy involves searching for genotype-selective anti-tumor agents that become lethal to tumor cells only in the presence of specific oncoproteins or in the absence of specific tumor suppressors.
Such genotype-selective compounds might target oncoproteins directly or they might target other critical proteins involved in oncoprotein-linked signaling networks. Using a synthetic lethal screening method, particularly a synthetic lethal high-throughout screening method, which is useful to identify agents or drugs for treating or preventing conditions or diseases such as the presence or development of tumors or other conditions characterized by hyperproliferation of cells e.
