Pharmacology of Modulators of Alternative Splicing

Bates, David O.; Morris, Jonathan C.; Oltean, Sebastian; Donaldson, Lucy F.

doi:10.1124/pr.115.011239

Cited by 76 publications

(62 citation statements)

References 158 publications

(205 reference statements)

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“…The identification of functionally important pathologic RNA variants opens up the possibility of therapeutic interventions targeting RNA variants or RNA variation-associated factors in cancers. Thus, regulation of RNA variations could be an effective therapeutic approach for cancer therapy, and a number of approaches have been taken to develop compounds that can experimentally, and sometimes clinically, affect splicing control, resulting in potential novel therapeutics 101 . Therefore, in cancers, changes in the levels of both RNA variants and RNA variation-associated factors are likely to be potential molecular markers for cancer diagnosis and may provide new targets for research and contribute to the development of clinical molecular targeted therapies.…”

Section: Resultsmentioning

confidence: 99%

Pathogenic diversity of RNA variants and RNA variation-associated factors in cancer development

Yang

Nam

2020

Exp Mol Med

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Recently, with the development of RNA sequencing technologies such as next-generation sequencing (NGS) for RNA, numerous variations of alternatively processed RNAs made by alternative splicing, RNA editing, alternative maturation of microRNA (miRNA), RNA methylation, and alternative polyadenylation have been uncovered. Furthermore, abnormally processed RNAs can cause a variety of diseases, including obesity, diabetes, Alzheimer's disease, and cancer. Especially in cancer development, aberrant RNAs caused by deregulated RNA modifiers or regulators are related to progression. Accumulating evidence has reported that aberrant RNAs promote carcinogenesis in many cancers, including liver cancer, leukemia, melanoma, lung cancer, breast cancer, and other cancers, in which abnormal RNA processing occurs in normal cells. Therefore, it is necessary to understand the precise roles and mechanisms of disease-related RNA processing in various cancers for the development of therapeutic interventions. In this review, the underlying mechanisms of variations in the RNA life cycle and the biological impacts of RNA variations on carcinogenesis will be discussed, and therapeutic strategies for the treatment of tumor malignancies will be provided. We also discuss emerging roles of RNA regulators in hepatocellular carcinogenesis.

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Section: Resultsmentioning

confidence: 99%

Pathogenic diversity of RNA variants and RNA variation-associated factors in cancer development

Yang

Nam

2020

Exp Mol Med

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“…In most cases, SR proteins work as activators, while hnRNPs act as suppressors. However, these RBPs can play either role in a context-dependent manner [67]. Aberrant splicing is often implicated in severe diseases such as cancer, Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA).…”

Section: Pre-mrna Splicing and Smamentioning

confidence: 99%

RNA-Targeted Therapies and High-Throughput Screening Methods

Zhu

Rooney

Michlewski

2020

IJMS

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RNA-binding proteins (RBPs) are involved in regulating all aspects of RNA metabolism, including processing, transport, translation, and degradation. Dysregulation of RNA metabolism is linked to a plethora of diseases, such as cancer, neurodegenerative diseases, and neuromuscular disorders. Recent years have seen a dramatic shift in the knowledge base, with RNA increasingly being recognised as an attractive target for precision medicine therapies. In this article, we are going to review current RNA-targeted therapies. Furthermore, we will scrutinise a range of drug discoveries targeting protein-RNA interactions. In particular, we will focus on the interplay between Lin28 and let-7, splicing regulatory proteins and survival motor neuron (SMN) pre-mRNA, as well as HuR, Musashi, proteins and their RNA targets. We will highlight the mechanisms RBPs utilise to modulate RNA metabolism and discuss current high-throughput screening strategies. This review provides evidence that we are entering a new era of RNA-targeted medicine.

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“…Создание новых биологически активных веществ -динамично развивающаяся область, постоянно претерпевающая как количественные, так и качественные изменения. Появляются новые термины, характеризующие биологическую активность, например, "Drugs Modulating Gene Expression", "Transcription Factor Ligands", "Translation Initiation Factor Inhibitors" [51] или "Modulators of Alternative Splicing" [65], и др. Усложняется наше понимание связей между молекулярными механизмами действия и вызываемыми ими фармакотерапевтическими эффектами, что привело к появлению и развитию «сетевой фармакологии» [66].…”

Section: интерпретация результатов прогноза Passunclassified

Computer-aided prediction of biological activity spectra for chemical compounds: opportunities and limitation

Филимонов

Druzhilovskiy

Lagunin

et al. 2018

BMCRM

134

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An essential characteristic of chemical compounds is their biological activity since its presence can become the basis for the use of the substance for therapeutic purposes, or, on the contrary, limit the possibilities of its practical application due to the manifestation of side action and toxic effects. Computer assessment of the biological activity spectra makes it possible to determine the most promising directions for the study of the pharmacological action of particular substances, and to filter out potentially dangerous molecules at the early stages of research. For more than 25 years, we have been developing and improving the computer program PASS (Prediction of Activity Spectra for Substances), designed to predict the biological activity spectrum of substance based on the structural formula of its molecules. The prediction is carried out by the analysis of structure-activity relationships for the training set, which currently contains information on structures and known biological activities for more than one million molecules. The structure of the organic compound is represented in PASS using Multilevel Neighborhoods of Atoms descriptors; the activity prediction for new compounds is performed by the naive Bayes classifier and the structure-activity relationships determined by the analysis of the training set. We have created and improved both local versions of the PASS program and freely available web resources based on PASS (http://www.way2drug.com). They predict several thousand biological activities (pharmacological effects, molecular mechanisms of action, specific toxicity and adverse effects, interaction with the unwanted targets, metabolism and action on molecular transport), cytotoxicity for tumor and non-tumor cell lines, carcinogenicity, induced changes of gene expression profiles, metabolic sites of the major enzymes of the first and second phases of xenobiotics biotransformation, and belonging to substrates and/or metabolites of metabolic enzymes. The web resource Way2Drug is used by over 18,000 researchers from more than 90 countries around the world, which allowed them to obtain over 600,000 predictions and publish about 500 papers describing the obtained results. The analysis of the published works shows that in some cases the interpretation of the prediction results presented by the authors of these publications requires an adjustment. In this work, we provide the theoretical basis and consider, on particular examples, the opportunities and limitations of computer-aided prediction of biological activity spectra.

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Pharmacology of Modulators of Alternative Splicing

Cited by 76 publications

References 158 publications

Pathogenic diversity of RNA variants and RNA variation-associated factors in cancer development

Pathogenic diversity of RNA variants and RNA variation-associated factors in cancer development

RNA-Targeted Therapies and High-Throughput Screening Methods

Computer-aided prediction of biological activity spectra for chemical compounds: opportunities and limitation

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