title: Linking tumor cell cytotoxicity to mechanism of drug action: an integrated analysis of gene expression, small-molecule screening and structural databases.
abstract: An integrated, bioinformatic analysis of three databases comprising tumor-cell-based small molecule screening data, gene expression measurements, and PDB (Protein Data Bank) ligand-target structures has been developed for probing mechanism of drug action (MOA). Clustering analysis of GI50 profiles for the NCI's database of compounds screened across a panel of tumor cells (NCI60) was used to select a subset of unique cytotoxic responses for about 4000 small molecules. Drug-gene-PDB relationships for this test set were examined by correlative analysis of cytotoxic response and differential gene expression profiles within the NCI60 and structural comparisons with known ligand-target crystallographic complexes. A survey of molecular features within these compounds finds thirteen conserved Compound Classes, each class exhibiting chemical features important for interactions with a variety of biological targets. Protein targets for an additional twelve Compound Classes could be directly assigned using drug-protein interactions observed in the crystallographic database. Results from the analysis of constitutive gene expressions established a clear connection between chemo-resistance and overexpression of gene families associated with the extracellular matrix, cytoskeletal organization, and xenobiotic metabolism. Conversely, chemo-sensitivity implicated overexpression of gene families involved in homeostatic functions of nucleic acid repair, aryl hydrocarbon metabolism, heat shock response, proteasome degradation and apoptosis. Correlations between chemo-responsiveness and differential gene expressions identified chemotypes with nonselective (i.e., many) molecular targets from those likely to have selective (i.e., few) molecular targets. Applications of data mining strategies that jointly utilize tumor cell screening, genomic, and structural data are presented for hypotheses generation and identifying novel anticancer candidates.
authors.affiliation: National Cancer Institute-Frederick, Developmental Therapeutics Program, Screening Technologies Branch, Laboratory of Computational Technologies, Frederick, Maryland, USA. covell@ncifcrf.gov
authors.forename: David G
authors.initials: DG
authors.lastname: Covell
authors.forename: Anders
authors.initials: A
authors.lastname: Wallqvist
authors.forename: Ruili
authors.initials: R
authors.lastname: Huang
authors.forename: Narmada
authors.initials: N
authors.lastname: Thanki
authors.forename: Alfred A
authors.initials: AA
authors.lastname: Rabow
authors.forename: Xiang-Jun
authors.initials: XJ
authors.lastname: Lu
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D014158:Transcription, Genetic
chemical_list: D000970:Antineoplastic Agents