Master Regulators Connectivity Map: A Transcription Factors-Centered Approach to Drug Repositioning

Abstract

Drug discovery is a very expensive and time-consuming endeavor. Fortunately, recent omics technologies and Systems Biology approaches introduced interesting new tools to achieve this task, facilitating the repurposing of already known drugs to new therapeutic assignments using gene expression data and bioinformatics. The inherent role of transcription factors in gene expression modulation makes them strong candidates for master regulators of phenotypic transitions. However, transcription factors expression itself usually does not reflect its activity changes due to post-transcriptional modifications and other complications. In this aspect, the use of high-throughput transcriptomic data may be employed to infer transcription factors-targets interactions and assess their activity through co-expression networks, which can be further used to search for drugs capable of reverting the gene expression profile of pathological phenotypes employing the connectivity maps paradigm. Following this idea, we argue that a module-oriented connectivity map approach using transcription factors-centered networks would aid the query for new repositioning candidates. Through a brief case study, we explored this idea in bipolar disorder, retrieving known drugs used in the usual clinical scenario as well as new candidates with potential therapeutic application in this disease. Indeed, the results of the case study indicate just how promising our approach may be to drug repositioning.

Cyclic AMP in dendritic cells: A novel potential target for disease‐modifying agents in asthma and other allergic disorders

“…The recent findings noted just above suggest that one might direct therapy at a target downstream of cAMP, for example the transcription factor IRF4. However, therapeutic approaches targeted at transcription factors have been challenging (De Bastiani, Pfaffenseller, & Klamt, 2018; Lambert, Jambon, Depauw, & David‐Cordonnier, 2018; Lee et al, 2020; Papavassiliou & Papavassiliou, 2016). Another approach might be to target genes and proteins regulated by such transcription factors and that link the increase in cAMP to functional activities in dendritic cells.…”

Integrated transcriptomics reveals master regulators of lung adenocarcinoma and novel repositioning of drug candidates

“…Altered regulatory units in lung adenocarcinoma were queried for drug candidates capable of reverting their expression profiles using a module‐oriented adaptation of classical connectivity maps (CMap) method of drug repositioning . Briefly, for each case‐control study in both TN references, inferred genes of several regulons were selected, combined, and their logFC values submitted to the CMap analysis workflow using PharmacoGx package (version 1.10.3) …”

Repurposing Drugs via Network Analysis: Opportunities for Psychiatric Disorders

“…Given the key contribution of transcription factors in the modulation of gene expression and driving phenotypic perturbations, the transcriptional regulome has been employed by De Bastiani et al for drug repurposing in bipolar disorders [ 91 ]. Their study inferred transcription factors–targets interactions via a reverse-engineering prediction algorithm applied on human prefrontal cortex microarray data.…”