INHIBITORS OF dUTPase
AssigneeUniversity of Southern California
InventorsRobert D. Ladner, Nouri Neamati
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Abstract
Evidence demonstrating that elevated expression of dUTPase protects breast cancer cells from the expansion of the intracellular uracil pool, translating to reduced growth inhibition following treatment with 5-FU is provided. The implementation of in silica drug development techniques to identify and develop small molecule inhibitors of dUTPase are reported. As 5-FU and the oral 5-FU pro-drug capecitabine remain central agents in the treatment of a variety of malignancies, the clinical utility of a small molecule inhibitor to dUTPase represents a viable strategy to improve the clinical efficacy of these mainstay chemotherapeutic agents.
Claims24
A composition comprising a deoxyuridine triphosphosphate nucleotidohydrolase (dUTPase) inhibitor that decreases the expression of dUTPase and increases the ability of the fluoropyrimidine class of anticancer agents to break DNA strands and thereby increases the cytotoxicity of cancer cells.
A method of increasing the cytotoxicity of a cancer cell by contacting said cancer cell with a composition comprising a dUTPase inhibitor, wherein said cancer cell exhibits dUTPase overexpression.
A composition comprising a dUTPase inhibitor that directly inhibits dUTPase and promotes dUTP accumulation and uracil-misincorporation thereby synergistically improving the clinical efficacy of thymidylate synthase (TS)-directed chemotherapy.
A method of synergistically improving the clinical efficacy of thymidylate TS-directed chemotherapy comprising contacting a cancer cell with a composition comprising a dUTPase inhibitor, wherein said cancer cell exhibits dUTPase overexpression.
A composition comprising a dUTPase inhibitor that directly inhibits dUTPase and promotes dUTP accumulation thereby decreases TS-directed drug resistance.
A method of decreasing TS-directed drug resistance comprising contacting a cancer cell with a composition comprising a dUTPase inhibitor, wherein said cancer cell exhibits dUTPase overexpression.
A composition comprising a dUTPase inhibitor that synergistically improves the efficacy of 5-fluorouracil (5-FU)-based chemotherapies in a wide variety of cancers, wherein said wide variety of cancers exhibits an overexpression of dUTPase.
A method of synergistically improving the efficacy of 5-fluorouracil (5-FU)-based chemotherapies in a wide variety of cancers comprising contacting said variety of cancer cells with a composition comprising a dUTPase inhibitor and wherein said variety of cancer cell exhibits dUTPase overexpression.
The method according to claim 23, wherein said dUTPase inhibitor is DU7, DU6, BB37, or DU44.
A method of screening for dUTPase inhibitors comprising:
- generating a pharmacophore model of the dUTPase enzyme bound to a dUDP substrate;
- perform docking studies with the dUTPase pharmacophore model against potential dUTPase antagonists;
- predict docking scores of potential dUTPase antagonists;
- and
- perform enzyme assay with candidate molecules displaying efficient contact with the dUTPase active site.
Dependencies are inferred from the claim text.