Method for Screening for Compounds Selectively Interacting with RAD9

Abstract

Natural and synthetic compounds of Formulae Ia-Ie having a lactone structure, in particular Securolide, have been determined to be effective anti-tumor compounds which target the hrad9 gene and/or protein encoded thereby or complex containing the protein and/or the p53 gene and/or protein. Securolide is cytoselective for mutants of hRad9 based on studies conducted in Rad9 mutant yeast strains. Securolide appears to interact with mutant hRad9 in cancer cells to produce DNA lesions which result in apoptosis. Studies have demonstrated that Securolide is useful for treating proliferation disorders such as melanoma, leukemia, breast cancer, lung cancer, ovarian cancer, colon cancer, esophagus cancer, liver cancer, and lymphatic cancer, and to alleviate pain associated with the cancer. Other compounds effective for the treatment of cancer and optionally pain associated therewith may also be identified using the same assays, for example, by screening for efficacy in assays using Rad9 and/or p53 defective mutant yeasts.

We claim: 
     
         1 . A method for screening for pharmaceutically active compounds comprising
 (a) providing cells having one or more mutations in the cell cycle checkpoint protein complex that includes Rad9, or a gene encoding a protein in the complex,   (b) adding a compound to be screened to the cells, and   (c) determining if the compound kills or induces apoptosis in some or all of the cells, and   (d) comparing the resultant determination of step (c) to the resultant determination induced by the compound in normal cells not having the one or more mutations in (a) to determine if the compound has anti-cancer activity.   
     
     
         2 . The method of  claim 1  wherein the cells are yeast cells. 
     
     
         3 . The method of  claim 1  wherein the cells are mammalian cells. 
     
     
         4 . The method of  claim 1  wherein the cells are in an animal. 
     
     
         5 . The method of  claim 1  wherein the cells are tumor cells. 
     
     
         6 . The method of  claim 1  further comprising adding the compound to normal cells not having a mutation in the cell cycle checkpoint protein complex including Rad9. 
     
     
         7 . The method of  claim 1  wherein the cells have a mutation in the Rad9 gene. 
     
     
         8 . The method of  claim 1  wherein the cells have an inactive or less active Rad9 protein. 
     
     
         9 . A pharmaceutically acceptable compound identified by the method of  claim 1 . 
     
     
         10 . A method for screening for pharmaceutically active compounds comprising
 (a) providing cells having one or more mutations in the protein p53, or a gene encoding the protein,   (b) adding a compound to be screened to the cells, and   (c) determining if the compound kills or induces apoptosis in some or all of the cells.   
     
     
         11 . The method of  claim 10  wherein the cells are yeast cells. 
     
     
         12 . The method of  claim 10  wherein the cells are mammalian cells. 
     
     
         13 . The method of  claim 10  wherein the cells are in an animal. 
     
     
         14 . The method of  claim 10  wherein the cells are tumor cells. 
     
     
         15 . The method of  claim 10  further comprising adding the compound to normal cells not having a mutation in the p53 protein. 
     
     
         16 . The method of  claim 10  wherein the cells have a mutation in the p53 gene. 
     
     
         17 . The method of  claim 10  wherein the cells have an inactive or less active p53 protein. 
     
     
         18 . A pharmaceutically acceptable compound identified by the method of  claim 10 .