The resurgence of phenotypic screening in drug discovery and development

Wagner, Bridget K.

doi:10.1517/17460441.2016.1122589

Cited by 45 publications

(32 citation statements)

References 28 publications

(31 reference statements)

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“…Before diving into recent advances in technology, we briefly describe the early stage of drug discovery in a historical perspective. Two crucial types of screening methods were pioneered and developed in the 1980s: target-based screens, which focus on a specific protein of interest reviewed by Croston (2017), and phenotypic screens, which concentrate on the disease state to be treatedreviewed by Wagner (2016). Target-based high-throughput screening (HTS) strategies for drug discovery kicked off in the early 1980s (Pereira & Williams, 2007) (Fig.…”

Section: Evolution Of Screening Technologies For Drug Discoverymentioning

confidence: 99%

“…Regardless of the particular approach, inhibitor development with small-molecule HTS approaches depends on the solubility of chemical moieties (Erlanson, 2012). This has prompted the use of phenotypic screens to initialize screening (Wagner, 2016), and is one of the driving forces behind the field of peptidomimetics, which aims to utilize favorable qualities of peptides, including aqueous solubility, membrane permeability and internalization capacity, while maintaining the ability to interact with proteins and avoiding degradation through proteolysis (Vagner, Qu, & Hruby, 2008). Peptide libraries have also been generated via solid-phase synthesis (Bessette, Rice, & Daugherty, 2004;Kenrick & Daugherty, 2010;Ryvkin et al, 2018;Sidhu, 2000), by covalently linking peptides to a resin and conducting the synthesis in the immobilized form (Fields, 2002).…”

Section: Dna-encoded Compound Libraries (Decls)mentioning

confidence: 99%

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Emerging drug development technologies targeting ubiquitination for cancer therapeutics

Veggiani

Gerpe

Sidhu

et al. 2019

Pharmacology & Therapeutics

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a b s t r a c t a r t i c l e i n f o Development of effective cancer therapeutic strategies relies on our ability to interfere with cellular processes that are dysregulated in tumors. Given the essential role of the ubiquitin proteasome system (UPS) in regulating a myriad of cellular processes, it is not surprising that malfunction of UPS components is implicated in numerous human diseases, including many types of cancer. The clinical success of proteasome inhibitors in treating multiple myeloma has further stimulated enthusiasm for targeting UPS proteins for pharmacological intervention in cancer treatment, particularly in the precision medicine era. Unfortunately, despite tremendous efforts, the paucity of potent and selective UPS inhibitors has severely hampered attempts to exploit the UPS for therapeutic benefits. To tackle this problem, many groups have been working on technology advancement to rapidly and effectively screen for potent and specific UPS modulators as intracellular probes or early-phase therapeutic agents. Here, we review several emerging technologies for developing chemical-and protein-based molecules to manipulate UPS enzymatic activity, with the aim of providing an overview of strategies available to target ubiquitination for cancer therapy.

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Section: Evolution Of Screening Technologies For Drug Discoverymentioning

confidence: 99%

Section: Dna-encoded Compound Libraries (Decls)mentioning

confidence: 99%

Emerging drug development technologies targeting ubiquitination for cancer therapeutics

Veggiani

Gerpe

Sidhu

et al. 2019

Pharmacology & Therapeutics

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“…Conducting a phenotypic screen followed by target deconvolution of novel hits constitutes an attractive strategy for the discovery of molecularly targeted therapies (Jung & Kwon, 2015). Indeed, the resurgence of phenotypic screening in early drug discovery (Eggert, 2013;Lee & Berg, 2013;Lee & Bogyo, 2013;Wagner, 2016) has increased the need for molecular target prediction methods. Target prediction, also known as target fishing, target deconvolution, drug-target interaction prediction or polypharmacology prediction (Byrne & Schneider, 2019;Cereto-Massagué et al, 2015;Ganesan & Barakat, 2016;Lavecchia & Cerchia, 2015;Pahikkala et al, 2015;Peón, Dang, & Ballester, 2016;Wang & Xie, 2014), aims at predicting the macromolecular targets of a given molecule (the query molecule).…”

Section: Introductionmentioning

confidence: 99%

MolTarPred: A web tool for comprehensive target prediction with reliability estimation

Peón

Ghislat

et al. 2019

Chem Biol Drug Des

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Molecular target prediction can provide a starting point to understand the efficacy and side effects of phenotypic screening hits. Unfortunately, the vast majority of in silico target prediction methods are not available as web tools. Furthermore, these are limited in the number of targets that can be predicted, do not estimate which target predictions are more reliable and/or lack comprehensive retrospective validations. We present MolTarPred ( http://moltarpred.marseille.inserm.fr/), a user‐friendly web tool for predicting protein targets of small organic compounds. It is powered by a large knowledge base comprising 607,659 compounds and 4,553 macromolecular targets collected from the ChEMBL database. In about 1 min, the predicted targets for the supplied molecule will be listed in a table. The chemical structures of the query molecule and the most similar compounds annotated with the predicted target will also be shown to permit visual inspection and comparison. Practical examples of the use of MolTarPred are showcased. MolTarPred is a new resource for scientists that require a more complete knowledge of the polypharmacology of a molecule. The introduction of a reliability score constitutes an attractive functionality of MolTarPred, as it permits focusing experimental confirmatory tests on the most reliable predictions, which leads to higher prospective hit rates.

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“…Further, the cellular context (i.e., subcellular location, post-translational modifications, levels of metabolites, and interactions with other proteins) is important for the function of proteins and is lost when working with purified proteins. These limitations have led, in recent years, to an renewed interest in phenotypic screening [4–6]. In this strategy, a particular trait or phenotype is sought in live cells (e.g., induction of cell death in cancer cells).…”

Section: Introductionmentioning

confidence: 99%

Thermal proteome profiling: unbiased assessment of protein state through heat-induced stability changes

2016

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In recent years, phenotypic-based screens have become increasingly popular in drug discovery. A major challenge of this approach is that it does not provide information about the mechanism of action of the hits. This has led to the development of multiple strategies for target deconvolution. Thermal proteome profiling (TPP) allows for an unbiased search of drug targets and can be applied in living cells without requiring compound labeling. TPP is based on the principle that proteins become more resistant to heat-induced unfolding when complexed with a ligand, e.g., the hit compound from a phenotypic screen. The melting proteome is also sensitive to other intracellular events, such as levels of metabolites, post-translational modifications and protein-protein interactions. In this review, we describe the principles of this approach, review the method and its developments, and discuss its current and future applications. While proteomics has generally focused on measuring relative protein concentrations, TPP provides a novel approach to gather complementary information on protein stability not present in expression datasets. Therefore, this strategy has great potential not only for drug discovery, but also for answering fundamental biological questions.

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The resurgence of phenotypic screening in drug discovery and development

Cited by 45 publications

References 28 publications

Emerging drug development technologies targeting ubiquitination for cancer therapeutics

Emerging drug development technologies targeting ubiquitination for cancer therapeutics

MolTarPred: A web tool for comprehensive target prediction with reliability estimation

Thermal proteome profiling: unbiased assessment of protein state through heat-induced stability changes

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