Document Detail

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.
MedLine Citation:
PMID:  21335596     Owner:  NLM     Status:  MEDLINE    
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.
Hui-Fang Li; Adam Keeton; Michele Vitolo; Clinton Maddox; Lynn Rasmussen; Judith Hobrath; E Lucille White; Ben Ho Park; Gary A Piazza; Jung-Sik Kim; Todd Waldman
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-02-18
Journal Detail:
Title:  Journal of biomolecular screening     Volume:  16     ISSN:  1552-454X     ISO Abbreviation:  J Biomol Screen     Publication Date:  2011 Apr 
Date Detail:
Created Date:  2011-04-07     Completed Date:  2011-08-01     Revised Date:  2014-09-21    
Medline Journal Info:
Nlm Unique ID:  9612112     Medline TA:  J Biomol Screen     Country:  United States    
Other Details:
Languages:  eng     Pagination:  383-93     Citation Subset:  IM    
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MeSH Terms
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
Cell Line, Tumor
Cell Proliferation / drug effects
Cyclin D / metabolism
Cyclin-Dependent Kinase Inhibitor p27 / metabolism
DNA Damage / drug effects
Drug Screening Assays, Antitumor
HCT116 Cells
High-Throughput Screening Assays*
Indoles / pharmacology*
Mutation / genetics
Neoplasms / genetics*
PTEN Phosphohydrolase / genetics*
Phosphatidylinositol 3-Kinases / genetics*
Proto-Oncogene Proteins c-akt / metabolism
Reproducibility of Results
Sulfonamides / pharmacology*
Grant Support
R01 CA115699/CA/NCI NIH HHS; R01 CA115699/CA/NCI NIH HHS; R01 CA115699-05/CA/NCI NIH HHS; R03 NS050857/NS/NINDS NIH HHS; R03 NS050857/NS/NINDS NIH HHS; R03 NS050857-01/NS/NINDS NIH HHS; U54 HG003917/HG/NHGRI NIH HHS
Reg. No./Substance:
0/Antineoplastic Agents; 0/CID1340132; 0/Cyclin D; 0/Indoles; 0/Sulfonamides; 147604-94-2/Cyclin-Dependent Kinase Inhibitor p27; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC protein, human; EC Proteins c-akt; EC protein, human; EC Phosphohydrolase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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