Evaluating biological activity of compounds by transcription factor activity profiling

Medvedev, Alexander V.; Moeser, Matt; Medvedeva, Liubov; Martsen, Elena; Granick, Alexander; Raines, Lydia; Zeng, Ming; Makarov, Sergei S.; Houck, Keith A.

doi:10.1126/sciadv.aar4666

Cited by 21 publications

(45 citation statements)

References 60 publications

(52 reference statements)

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“…6B). At the concentration of 2.2 uM, the Ulixertinib signature had a higher similarity to the Raf PKI consensus signature; at 6.7 uM, it matched the consensus TFAP signature of mitochondria inhibitors 11 .…”

Section: Resultsmentioning

confidence: 94%

“…6A). However, at a higher concentration (6.7 uM), the GDC-0994 signature had a high similarity to the consensus TFAP signature of histone deacetylase (HDAC) inhibitors 11 .…”

Section: Resultsmentioning

confidence: 99%

“…Previously, we showed characteristic TFAP signatures for perturbations of various biological processes and cell systems, including inhibitors of mitochondria function and Ub/PS protein degradation pathway, histone deacetylation, DNA damaging agents, and cytoskeleton disruptors 11 . The present work expands this list by the characteristic TFAP signatures for kinase inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…Our approach is based on the premise that protein kinases lie at the heart of signal transduction pathways. Furthermore, as we demonstrated previously, perturbagens of various biological processes and cell systems cause coordinated changes in the activity of signaling pathways, epitomized by specific TF activity profiles (TFAP) 11 . Thus, we sought to determine if cells' response to kinase inhibitors, too, can be described by specific TFAP signatures.…”

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confidence: 86%

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Illuminating kinase inhibitors biology by cell signaling profiling

Medvedev

Medvedeva

Martsen

et al. 2022

Preprint

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Protein kinase inhibitors (PKI) evolved as promising drugs for multiple diseases. However, PKIs’ promiscuity causes polypharmacological effects challenging therapeutic development. We show that the polypharmacology of PKIs can be inferred from their impact on transcription factors (TF) lying at the apexes of signaling pathways. Using a high-content reporter assay, we evaluated TF activity profiles (TFAP) in cells treated with Akt, CDK, Aurora, Raf, MEK, and ERK inhibitors. In each case, we found kinase-specific consensus TFAP signatures signifying the on-target PKI activity. Remarkably, proximal kinases had the highest similarity values of their PKIs’ consensus signatures. Furthermore, we show that individual PKIs exhibited the consensus, “on-target signatures” within certain “specificity windows” and distinct “off-target signatures” at other concentrations. We also show that the off-target PKI signatures permit pinpointed the underlying biological effects. Therefore, the TFAP approach provides clear-cut quantitative metrics for assessing the dominant PKI activity and concentration ranges where the on-target activity dominates cell response. Thus, this effect-based approach illuminates PKI biology invisible to target-based techniques streamlining the selection of kinase chemical probes and PKI drug prioritization.

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Section: Resultsmentioning

confidence: 94%

“…6A). However, at a higher concentration (6.7 uM), the GDC-0994 signature had a high similarity to the consensus TFAP signature of histone deacetylase (HDAC) inhibitors 11 .…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 86%

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Illuminating kinase inhibitors biology by cell signaling profiling

Medvedev

Medvedeva

Martsen

et al. 2022

Preprint

Self Cite

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show abstract

“…Because TFs control the expression of multiple genes, analyzing and manipulating TF activity is promising for regulating various biological processes. TF profiling is also useful for high-throughput analysis of the effects and side effects of biochemicals ( Medvedev et al., 2018 ); thus, our current method will be useful in assessing the effect of biochemicals in vivo . Because aberrant regulation of transcription factors is suggested to be involved in the pathophysiology of many diseases ( Ebert and Greenberg, 2013 ; Lambert et al., 2018 ; Lee and Young, 2013 ; Maurano et al., 2012 ), analyzing the activity state of TFs will be helpful in developing effective treatments.…”

Section: Discussionmentioning

confidence: 99%