On-Target Side Effects of Targeted Therapeutics of Cancer

Tı́már, József; Uhlyarik, Andrea

doi:10.3389/pore.2022.1610694

Cited by 11 publications

(3 citation statements)

References 50 publications

(154 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4,5 Prioritizing specific downstream mediators is critical to minimize safety signals and ensure adherence to a life-long pharmacotherapy. 5,6 Recent advances in human genetics have enabled an in silico prioritization of drug targets 7,8 , with approval rates more than two times higher than targets without genetic support. 9 Mendelian randomization (MR) uses data from genome-wide association studies (GWAS) and offers a statistical framework for exploring associations between variants in genes encoding drug targets and disease traits.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Genomic Architecture of Circulating Cytokine Levels Points to Drug Targets for Immune-Related Diseases

Konieczny,

Omarov,

Malik

et al. 2024

Preprint

View full text Add to dashboard Cite

Circulating cytokines orchestrate immune reactions and are promising drug targets for immune-mediated and inflammatory diseases. Exploring the genetic architecture of circulating cytokine levels could yield key insights into causal mediators of human disease. Here, we performed genome-wide association studies (GWAS) for 40 circulating cytokines in meta-analyses of 74,783 individuals. We detected 359 significant associations between cytokine levels and variants in 169 independent loci, including 150 trans- and 19 cis-acting loci. Integration with transcriptomic data point to key regulatory mechanisms, such as the buffering function of ACKR1 acting as scavenger for multiple chemokines and the role of TRAFD1 in modulating the cytokine storm triggered by TNF signaling. Applying Mendelian randomization (MR), we detected a network of complex cytokine interconnections with TNF-b, VEGF, and IL-1ra exhibiting pleiotropic downstream effects on multiple cytokines. Drug target cis-MR paired with colocalization revealed G-CSF/CSF-3 and CXCL9/MIG as potential causal mediators of asthma and Crohns disease, respectively, but also a potentially protective role of TNF-b in multiple sclerosis. Our results provide an overview of the genetic architecture of circulating cytokines and could guide the development of targeted immunotherapies.

show abstract

Section: Introductionmentioning

confidence: 99%

“…4,5 Prioritizing specific downstream mediators is critical to minimize safety signals and ensure adherence to a life-long pharmacotherapy. 5,6…”

Section: Introductionmentioning

confidence: 99%

The Genomic Architecture of Circulating Cytokine Levels Points to Drug Targets for Immune-Related Diseases

Konieczny,

Omarov,

Malik

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…by the disruption of essential cellular pathways. This effect is known as on-target toxicity [8, 9]. Often, however, drugs not only interact with their intended target protein, but also with other so-called off-targets, leading to possible side effects [7].…”

Section: Introductionmentioning

confidence: 99%

PanScreen: A Comprehensive Approach to Off-Target Liability Assessment

Sellner,

Lill,

Smieško

2023

Preprint

View full text Add to dashboard Cite

Drug development projects are getting increasingly more expensive while their success rate is stagnating. Safety issues attributed to off-target binding represent a major reason for the failure of new drugs. Besides desired on-target binding, small molecules may interact with off-targets, triggering adverse effects. Therefore, the development of novel methods for early recognition of such issues that are resource-efficient and cost-effective becomes vital. Here, we introduce PanScreen, an online platform for the automated assessment of off-target liabilities. PanScreen combines structure-based modeling techniques with state-of-the-art deep learning methods to not only predict accurate binding affinities but also give insight into potential modes of action. We show that the predictions are approaching experimental accuracy found in public datasets and that the same technology can also be used for other research areas, such as drug repurposing. Such fast and inexpensive methods allow researchers to test not only drug candidates, but all small molecules that might come into contact with a human organism for potential safety concerns very early in the development process. PanScreen is publicly available atwww.panscreen.ch.

show abstract

Tankyrase inhibition interferes with junction remodeling, induces leakiness, and disturbs YAP1/TAZ signaling in the endothelium

Ma,

Wibowo,

Wirtz

et al. 2023

Naunyn-Schmiedeberg's Arch Pharmacol

View full text Add to dashboard Cite

Tankyrase inhibitors are increasingly considered for therapeutic use in malignancies that are characterized by high intrinsic β-catenin activity. However, how tankyrase inhibition affects the endothelium after systemic application remains poorly understood. In this study, we aimed to investigate how the tankyrase inhibitor XAV939 affects endothelial cell function and the underlying mechanism involved. Endothelial cell function was analyzed using sprouting angiogenesis, endothelial cell migration, junctional dynamics, and permeability using human umbilical vein endothelial cells (HUVEC) and explanted mouse retina. Underlying signaling was studied using western blot, immunofluorescence, and qPCR in HUVEC in addition to luciferase reporter gene assays in human embryonic kidney cells. XAV939 treatment leads to altered junctional dynamics and permeability as well as impaired endothelial migration. Mechanistically, XAV939 increased stability of the angiomotin-like proteins 1 and 2, which impedes the nuclear translocation of YAP1/TAZ and consequently suppresses TEAD-mediated transcription. Intriguingly, XAV939 disrupts adherens junctions by inducing RhoA-Rho dependent kinase (ROCK)-mediated F-actin bundling, whereas disruption of F-actin bundling through the ROCK inhibitor H1152 restores endothelial cell function. Unexpectedly, this was accompanied by an increase in nuclear TAZ and TEAD-mediated transcription, suggesting differential regulation of YAP1 and TAZ by the actin cytoskeleton in endothelial cells. In conclusion, our findings elucidate the complex relationship between the actin cytoskeleton, YAP1/TAZ signaling, and endothelial cell function and how tankyrase inhibition disturbs this well-balanced signaling.

show abstract

On-Target Side Effects of Targeted Therapeutics of Cancer

Cited by 11 publications

References 50 publications

The Genomic Architecture of Circulating Cytokine Levels Points to Drug Targets for Immune-Related Diseases

The Genomic Architecture of Circulating Cytokine Levels Points to Drug Targets for Immune-Related Diseases

PanScreen: A Comprehensive Approach to Off-Target Liability Assessment

Tankyrase inhibition interferes with junction remodeling, induces leakiness, and disturbs YAP1/TAZ signaling in the endothelium

Contact Info

Product

Resources

About