High-Throughput Screening: Update on Practices and Success

Fox, Sandra; Farr-Jones, Shauna; Sopchak, Lynne; Boggs, Amy F; Nicely, Helen Wang; Khoury, Richard; Biros, Michael

doi:10.1177/1087057106292473

Cited by 190 publications

(113 citation statements)

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“…During the past decades most screening approaches for identification of new cancer drug candidates have utilized cell free assays for detection of specific interactions with known or emerging molecular targets [1]. However, the relatively poor outcome with respect to identification of clinically novel and significantly improved cancer drugs has led to a renewed and growing interest for cancer drug screening based on compound induced changes in cellular phenotypes [2].…”

Section: Introductionmentioning

confidence: 99%

Phenotype-based drug screening in primary ovarian carcinoma cultures identifies intracellular iron depletion as a promising strategy for cancer treatment

Gullbo

Fryknäs

Rickardson

et al. 2011

Biochemical Pharmacology

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. The results indicate the feasibility of using PCPTC for cancer drug screening and that intracellular iron depletion could be a potentially important strategy for cancer therapy.

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Section: Introductionmentioning

confidence: 99%

Phenotype-based drug screening in primary ovarian carcinoma cultures identifies intracellular iron depletion as a promising strategy for cancer treatment

Gullbo

Fryknäs

Rickardson

et al. 2011

Biochemical Pharmacology

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“…Most drug development methods rely on phenotypic and target-based HTS of synthetic chemical libraries to search for active compounds for further development into potent drugs, 4 but such synthetic libraries are often limited in structural diversity and novelty. Natural products offer an alternative source of highly underexplored chemical entities with privileged bioactive molecules that could be used as templates for the synthesis of novel drugs.…”

Section: Research-article2014mentioning

confidence: 99%

High-Throughput Screening Platform for Natural Product–Based Drug Discovery Against 3 Neglected Tropical Diseases: Human African Trypanosomiasis, Leishmaniasis, and Chagas Disease

et al. 2015

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African trypanosomiasis, leishmaniasis, and Chagas disease are 3 neglected tropical diseases for which current therapeutic interventions are inadequate or toxic. There is an urgent need to find new lead compounds against these diseases. Most drug discovery strategies rely on high-throughput screening (HTS) of synthetic chemical libraries using phenotypic and targetbased approaches. Combinatorial chemistry libraries contain hundreds of thousands of compounds; however, they lack the structural diversity required to find entirely novel chemotypes. Natural products, in contrast, are a highly underexplored pool of unique chemical diversity that can serve as excellent templates for the synthesis of novel, biologically active molecules. We report here a validated HTS platform for the screening of microbial extracts against the 3 diseases. We have used this platform in a pilot project to screen a subset (5976) of microbial extracts from the MEDINA Natural Products library. Tandem liquid chromatography-mass spectrometry showed that 48 extracts contain potentially new compounds that are currently undergoing de-replication for future isolation and characterization. Known active components included actinomycin D, bafilomycin B1, chromomycin A3, echinomycin, hygrolidin, and nonactins, among others. The report here is, to our knowledge, the first HTS of microbial natural product extracts against the above-mentioned kinetoplastid parasites.

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“…More use of primary cells for HTS is in the future. Strategies to design the assay to target multiple genes at the same time are required to attain a phenotype change by small molecules [11]. Whole animal testing via cassette dosing is a procedure adapted by HTS to rapidly access pharmacokinetics of many drugs.…”

Section: Futurementioning

confidence: 99%

High Throughput Screening of Small Molecule Library: Procedure, Challenges and Future

Shukla¹

2016

JCPCR

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High-throughput screening (HTS) of small molecules is used to identify and characterize chemical compounds based on their response on particular assays. The screened compounds can be further used as tools to study complex molecular pathways involved in progression of cancers and potential candidates can be further developed as drugs. Testing of vast number of compounds and fast readout technologies for assays in a timely manner has made this procedure a popular drug-discovery process, which is widely used in the pharmaceutical industry. However, the procedure of screening is a multi-step process and is prone to give false positive and false negative results. Assurance of quality and good analysis of results play critical role in finding a true product. Technological hardware like robotic plate handling is critical for the procedure. Reagents like antibodies and recombinant proteins can also make the whole procedure very expensive. Increased number of available compounds and molecular targets has raised the requirements for even faster procedures, more sensitive assays to run and even smaller sample size assays for screening. Development of new methods like Droplet-based cell encapsulation technology has given hope for a better future of HTS. Keywords: High-throughput screening (HTS); Small molecules; Target identification; Assay design IntroductionCancer kills around 7.6 million people worldwide every year and about a half million people in the US annually. Early detection and more effective chemotherapy have improved cure rate among patients. However, patients diagnosed with advanced stage cancers still have very few options for treatment. It has been shown that there are short and long term adverse effects of chemotherapy. Both adult and pediatric cancer survivors face significant health burdens including but not limited to impaired end-organ function, risk of secondary cancers and shortened life expectancies [1,2].Development of personalized medicine strategy is becoming more popular. It focuses on identifying drugs that can target a molecular pathway or more specifically a protein involved in an uncontrolled or disrupted signaling pathway leading to the progression of particular cancer. Genetics studies are confirming addictions and weaknesses of cancer cells on such pathways and specific molecules. With this approach, normal tissues are spared from getting targeted by toxic chemotherapies.Drug discovery programs start to find a cure for a disease, which does not have suitable treatment available. Data generated by primary research suggest involvement of specific proteins in the progression of diseases and can be used as target for drug development [3]. An assay is then developed that can be used to screen small molecule chemical libraries The whole process of HTS can be divided into steps of target identification, assay design, primary and secondary screens, data analysis and identification of hits (Figure 1). The role of HTS is not only limited to identifying new compounds but is also useful in ass...

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High-Throughput Screening: Update on Practices and Success

Cited by 190 publications

References 0 publications

Phenotype-based drug screening in primary ovarian carcinoma cultures identifies intracellular iron depletion as a promising strategy for cancer treatment

Phenotype-based drug screening in primary ovarian carcinoma cultures identifies intracellular iron depletion as a promising strategy for cancer treatment

High-Throughput Screening Platform for Natural Product–Based Drug Discovery Against 3 Neglected Tropical Diseases: Human African Trypanosomiasis, Leishmaniasis, and Chagas Disease

High Throughput Screening of Small Molecule Library: Procedure, Challenges and Future

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