title: A high-throughput screen with isogenic PTEN+/+ and PTEN-/- cells identifies CID1340132 as a novel compound that induces apoptosis in PTEN and PIK3CA mutant human cancer cells.
abstract: The PTEN tumor suppressor gene is one of the most commonly mutated genes in human cancer. Because inactivation of PTEN is a somatic event, PTEN mutations represent an important genetic difference between cancer cells and normal cells and therefore a potential anticancer drug target. However, it remains a substantial challenge to identify compounds that target loss-of-function events such as mutations of tumor suppressors. In an effort to identify small molecules that preferentially kill cells with mutations of PTEN, the authors developed and implemented a high-throughput, paired cell-based screen composed of parental HCT116 cells and their PTEN gene-targeted derivatives. From 138 758 compounds tested, two hits were identified, and one, N'-[(1-benzyl-1H-indol-3-yl)methylene]benzenesulfonohydrazide (CID1340132), was further studied using a variety of cell-based models, including HCT116, MCF10A, and HEC1A cells with targeted deletion of either their PTEN or PIK3CA genes. Preferential killing of PTEN and PIK3CA mutant cells was accompanied by DNA damage, inhibition of DNA synthesis, and apoptosis. Taken together, these data validate a cell-based screening approach for identifying lead compounds that target cells with specific tumor suppressor gene mutations and describe a novel compound with preferential killing activity toward PTEN and PIK3CA mutant cells.
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, DC 20007, USA.
authors.forename: Hui-Fang
authors.initials: HF
authors.lastname: Li
authors.forename: Adam
authors.initials: A
authors.lastname: Keeton
authors.forename: Michele
authors.initials: M
authors.lastname: Vitolo
authors.forename: Clinton
authors.initials: C
authors.lastname: Maddox
authors.forename: Lynn
authors.initials: L
authors.lastname: Rasmussen
authors.forename: Judith
authors.initials: J
authors.lastname: Hobrath
authors.forename: E Lucille
authors.initials: EL
authors.lastname: White
authors.forename: Ben Ho
authors.initials: BH
authors.lastname: Park
authors.forename: Gary A
authors.initials: GA
authors.lastname: Piazza
authors.forename: Jung-Sik
authors.initials: JS
authors.lastname: Kim
authors.forename: Todd
authors.initials: T
authors.lastname: Waldman
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases; D056741:Cyclin D / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D045325:HCT116 Cells; D057166:High-Throughput Screening Assays; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015203:Reproducibility of Results; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C559849:CID1340132; D056741:Cyclin D; D007211:Indoles; D013449:Sulfonamides; D050760:Cyclin-Dependent Kinase Inhibitor p27; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human