Evaluating biological activity of compounds by transcription factor activity profiling

Area of Science:

• Biomedical research
• Molecular biology
• Pharmacology

Background:

• Assessing compound biological activity is crucial in biomedical research.
• Transcription factors (TFs) regulate gene expression and are key targets.
• Existing methods may not fully capture complex cellular responses to compounds.

Purpose of the Study:

• To develop a method for inferring compound bioactivity by analyzing TF activity.
• To establish quantitative TF activity profiles (TFAPs) as signatures of cellular response.
• To demonstrate the utility of TFAPs in identifying compound bioactivities and perturbed pathways.

Main Methods:

• Utilized a multiplex reporter system named FACTORIAL.
• Characterized cellular response to compounds via quantitative TFAP signatures.
• Analyzed TFAP signatures for various classes of chemical perturbagens.

Main Results:

• Distinct TFAP signatures were observed for different biological pathway perturbations.
• Unexpectedly, compounds targeting the same pathway consistently produced identical TFAPs.
• Invariant TFAPs were identified for inhibitors of mitochondrial, histone deacetylase, and ubiquitin/proteasome pathways, as well as for cytoskeleton disruptors and DNA-damaging agents.

Conclusions:

• TF activity profiling provides a straightforward method to assess compound bioactivity.
• TFAP signatures enable the identification of perturbed biological pathways.
• This approach facilitates the characterization of uncharacterized compounds and the assessment of polypharmacological drugs.