Chemogenomics: an emerging strategy for rapid target and drug discovery

Bredel, Markus; Jacoby, Edgar

doi:10.1038/nrg1317

Cited by 339 publications

(234 citation statements)

References 120 publications

Supporting

Mentioning

227

Contrasting

Unclassified

Order By: Relevance

“…Chemogenomic strategies have proven useful to isolate chemical compounds that could induce a specific phenotype (14,15). In such approaches, also referred as chemical genetics, cells are tested against a library of small molecules using high-throughput screening and then examined for a desired phenotype (16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Parthenolide Inhibits Tubulin Carboxypeptidase Activity

et al. 2007

View full text Add to dashboard Cite

Microtubules are centrally involved in cell division, being the principal components of mitotic spindle. Tubulin, the constituent of microtubules, can be cyclically modified on its A-subunit by enzymatic removal of the COOH-terminal tyrosine residue by an ill-defined tubulin carboxypeptidase (TCP) and its readdition by tubulin tyrosine ligase (TTL). We and others have previously shown that suppression of TTL and resulting accumulation of detyrosinated tubulin are frequent in human cancers of poor prognosis. Explanations for the involvement of TTL and detyrosinated tubulin in tumor progression arise from the recent discovery that tubulin detyrosination leads to CAP-Gly protein mislocalization, which correlates with defects in spindle positioning during mitosis. Impaired control of spindle positioning is one factor favoring tumor invasiveness. Thus, TCP could be a target for developing novel therapeutic strategies against advanced stages of cancers. Inhibitors of TCP, by reversing abnormal detyrosinated tubulin accumulation in tumor cells, could impair tumor progression. TCP has never been isolated and this has hampered search of specific inhibitors. In this article, we describe a cell-based assay of TCP activity and its use to screen a library of natural extracts for their inhibitory potency. This led to the isolation of two sesquiterpene lactones. We subsequently found that parthenolide, a structurally related compound, can efficiently inhibit TCP. This inhibitory activity is a new specific property of parthenolide independent of its action on the nuclear factor-KB pathway. Parthenolide is also known for its anticancer properties. Thus, TCP inhibition could be one of the underlying mechanisms of these anticancer properties.

show abstract

Section: Introductionmentioning

confidence: 99%

Parthenolide Inhibits Tubulin Carboxypeptidase Activity

et al. 2007

View full text Add to dashboard Cite

show abstract

“…1 This paper addresses an issue which has been pointed out by several authors yet never fully explored. Correlations between compound activity and biological variables are used as descriptors of the compounds.…”

Section: Introductionmentioning

confidence: 94%

In Vitro Drug Sensitivity-Gene Expression Correlations Involve a Tissue of Origin Dependency

Andersson

Fryknäs

Rickardson

et al. 2006

J. Chem. Inf. Model.

View full text Add to dashboard Cite

A major concern of chemogenomics is to associate drug activity with biological variables. Several reports have clustered cell line drug activity profiles as well as drug activity-gene expression correlation profiles and noted that the resulting groupings differ but still reflect mechanism of action. The present paper shows that these discrepancies can be viewed as a weighting of drug−drug distances, the weights depending on which cell lines the two drugs differ in.

show abstract

“…Chemogenomics is therefore emerging as a useful strategy for target-based drug design 5 (see 'Drug discovery: from the genome to the clinic' , overleaf). This approach exploits both chemical (for example, protein structureactivity data and drug binding-site features) and genomic (DNA sequence) information about the pathogenic organism.…”

Section: From Lab To Clinicmentioning

confidence: 99%