Differential PROTAC substrate specificity dictated by orientation of recruited E3 ligase DOI Creative Commons
Blake E. Smith, Stephen L. Wang, Saul Jaime‐Figueroa

et al.

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: Jan. 4, 2019

Abstract PROteolysis-TArgeting Chimeras (PROTACs) are hetero-bifunctional molecules that recruit an E3 ubiquitin ligase to a given substrate protein resulting in its targeted degradation. Many potent PROTACs with specificity for dissimilar targets have been developed; however, the factors governing degradation selectivity within closely-related families remain elusive. Here, we generate isoform-selective p38 MAPK family using single warhead (foretinib) and recruited (von Hippel-Lindau). Based on their distinct linker attachments lengths, these two differentially VHL, of p38α or p38δ. We characterize role ternary complex formation driving selectivity, showing it is necessary, but insufficient, PROTAC-induced ubiquitination. Lastly, explore p38δ:PROTAC:VHL explain different profiles PROTACs. Our work attributes selective proteins same heretofore underappreciated aspects model.

Language: Английский

Drug repurposing: progress, challenges and recommendations DOI
Sudeep Pushpakom, Francesco Iorio, Patrick A. Eyers

et al.

Nature Reviews Drug Discovery, Journal Year: 2018, Volume and Issue: 18(1), P. 41 - 58

Published: Oct. 12, 2018

Language: Английский

Citations

3720
A Next Generation Connectivity Map: L1000 Platform and the First 1,000,000 Profiles DOI Creative Commons

Aravind Subramanian,

Rajiv Narayan,

Steven M. Corsello

et al.

Cell, Journal Year: 2017, Volume and Issue: 171(6), P. 1437 - 1452.e17

Published: Nov. 1, 2017

Language: Английский

Citations

2746
Skepinone-L, a Novel Potent and Highly Selective Inhibitor of p38 MAP Kinase, Effectively Impairs Platelet Activation and Thrombus Formation DOI Creative Commons
Oliver Borst,

Britta Walker,

Patrick Münzer

et al.

Cellular Physiology and Biochemistry, Journal Year: 2013, Volume and Issue: 31(6), P. 914 - 924

Published: Jan. 1, 2013

Until now, a lack of inhibitors with high potency and selectivity in vivo has hampered investigation the p38 mitogen-activated protein kinase (MAPK) signaling pathway. We describe design skepinone-L, which is, to our knowledge, first ATP-competitive MAPK inhibitor excellent efficacy selectivity. Therefore, skepinone-L is valuable probe for chemical biology research, it may foster development unique class inhibitors.

Language: Английский

Citations

1843
STITCH 5: augmenting protein–chemical interaction networks with tissue and affinity data DOI Creative Commons
Damian Szklarczyk, Alberto Santos, Christian von Mering

et al.

Nucleic Acids Research, Journal Year: 2015, Volume and Issue: 44(D1), P. D380 - D384

Published: Nov. 20, 2015

Interactions between proteins and small molecules are an integral part of biological processes in living organisms. Information on these interactions is dispersed over many databases, texts prediction methods, which makes it difficult to get a comprehensive overview the available evidence. To address this, we have developed STITCH ('Search Tool for Interacting Chemicals') that integrates disparate data sources 430 000 chemicals into single, easy-to-use resource. In addition increased scope database, implemented new network view gives user ability binding affinities interaction network. This enables quick potential effects chemical its partners. For each organism, provides global network; however, not all same pattern spatial expression. Therefore, only certain subset can occur simultaneously. new, fifth release STITCH, functionality filter out associated with given tissue. The database be downloaded full, accessed programmatically via extensive API, or searched redesigned web interface at http://stitch.embl.de.

Language: Английский

Citations

1351
DeepDTA: deep drug–target binding affinity prediction DOI Creative Commons
Hakime Öztürk, Arzucan Özgür,

Elif Özkırımlı

et al.

Bioinformatics, Journal Year: 2018, Volume and Issue: 34(17), P. i821 - i829

Published: July 14, 2018

The identification of novel drug-target (DT) interactions is a substantial part the drug discovery process. Most computational methods that have been proposed to predict DT focused on binary classification, where goal determine whether pair interacts or not. However, protein-ligand assume continuum binding strength values, also called affinity and predicting this value still remains challenge. increase in data available knowledge-bases allows use advanced learning techniques such as deep architectures prediction affinities. In study, we propose deep-learning based model uses only sequence information both targets drugs interaction few studies focus either 3D structures complexes 2D features compounds. One approach used work modeling protein sequences compound 1D representations with convolutional neural networks (CNNs). results show an effective for target prediction. which high-level are constructed via CNNs achieved best Concordance Index (CI) performance one our larger benchmark sets, outperforming KronRLS algorithm SimBoost, state-of-the-art method

Language: Английский

Citations

1140
Functional genomic landscape of acute myeloid leukaemia DOI
Jeffrey W. Tyner, Cristina E. Tognon, Daniel Bottomly

et al.

Nature, Journal Year: 2018, Volume and Issue: 562(7728), P. 526 - 531

Published: Oct. 1, 2018

Language: Английский

Citations

1137
Kinase-targeted cancer therapies: progress, challenges and future directions DOI Creative Commons
Khushwant S. Bhullar,

Naiara Orrego Lagarón,

Eileen McGowan

et al.

Molecular Cancer, Journal Year: 2018, Volume and Issue: 17(1)

Published: Feb. 15, 2018

The human genome encodes 538 protein kinases that transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these are associated with cancer initiation and progression. recent development small-molecule kinase inhibitors for the treatment diverse types has proven successful in clinical therapy. Significantly, second most targeted drug targets, after G-protein-coupled receptors. Since first inhibitor, early 1980s, 37 have received FDA approval malignancies such as breast lung cancer. Furthermore, about 150 kinase-targeted drugs phase trials, many kinase-specific preclinical stage development. Nevertheless, factors confound efficacy molecules. Specific tumor genetics, microenvironment, resistance, pharmacogenomics determine how useful compound will be given This review provides an overview discovery relation oncology highlights challenges future potential therapies.

Language: Английский

Citations

1058
The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands DOI Creative Commons
Christopher Southan, Joanna L Sharman, Helen E. Benson

et al.

Nucleic Acids Research, Journal Year: 2015, Volume and Issue: 44(D1), P. D1054 - D1068

Published: Oct. 12, 2015

The IUPHAR/BPS Guide to PHARMACOLOGY (GtoPdb, http://www.guidetopharmacology.org) provides expert-curated molecular interactions between successful and potential drugs their targets in the human genome. Developed by International Union of Basic Clinical Pharmacology (IUPHAR) British Pharmacological Society (BPS), this resource, its earlier incarnation as IUPHAR-DB, is described our 2014 publication. This update incorporates changes over intervening seven database releases. unique model content capture based on established new target class subcommittees collaborating with in-house curators. Most information comes from journal articles, but we now also index kinase cross-screening panels. Targets are specified UniProtKB IDs. Small molecules defined PubChem Compound Identifiers (CIDs); ligand includes peptides clinical antibodies. We have extended ligands linked via published quantitative binding data (e.g. Ki, IC50 or Kd). resulting pharmacological relationship network defines a data-supported druggable genome encompassing 7% proteins. an expanded substrate for biennially compendium, Concise PHARMACOLOGY. article covers increase, entity analysis, revised curation strategies, website features download options.

Language: Английский

Citations

1029
The role of ligand efficiency metrics in drug discovery DOI
Andrew L. Hopkins, György M. Keserű, Paul D. Leeson

et al.

Nature Reviews Drug Discovery, Journal Year: 2014, Volume and Issue: 13(2), P. 105 - 121

Published: Jan. 31, 2014

Language: Английский

Citations

1020
FDA-approved small-molecule kinase inhibitors DOI
Peng Wu, Thomas E. Nielsen, Mads H. Clausen

et al.

Trends in Pharmacological Sciences, Journal Year: 2015, Volume and Issue: 36(7), P. 422 - 439

Published: May 12, 2015

Language: Английский

Citations

916