Platforms

High Throughput Screening

Introduction

EDDC’s High Throughput Screening platform (HTS) can help you to identify hits or tool compounds for your target/cell of interest. Several compound libraries are available (from small focus sets to large diverse collection of more than 300,000 curated compounds) to better cater your needs. Boasting a state-of-the-art and the only fully integrated automation platform in Singapore, the HTS platform can screen up to 16,000 compounds per day per project. A variety of biochemical & functional cell-based assays offers researchers a wide range of selection to meet target specific assay read outs (absorbance, fluorescence, fluorescence polarisation, luminescence, FRET, nanoBRET, etc). We also support small molecule drug discovery projects in both EDDC and external parties with the primary goal of rapid identification of high-quality hit compounds, and to support their optimisations to patentable novel drug structures.

We screened and identified many precursor compounds that are successfully developed into preclinical candidates (PDCs) by EDDC and are ready to be licensed.


Case Studies

EDDC’s compound collection and drug discovery expertise enabled the identification of Singapore’s 1st publicly funded anti-cancer drug.

EDDC’s compound collection, although 10x smaller, is as diverse as collections at big pharma. We were able to uncover similar scaffolds by screening 230K compounds which is only 10% of 2M performed by a global top 10 pharma (e.g., GSK).

Discovery of WNT secretion inhibitor, ETC-159. A 225K compounds screening campaign followed by filtering through a series of specific assays lead to the identification of WNT secretion inhibitors.

Hits were identified from screening 225,755 compounds of diverse structures in EDDC. In-house chemists performed structure-activity relationship studies on these hits and optimised a novel scaffold which was patented and went on to clinical trials.

  •  References:
    • Soo Yei Ho, Jenefer Alam, Duraiswamy Athisayamani Jeyaraj, Weiling Wang, Grace Ruiting Lin, Shi Hua Ang, Eldwin Sum Wai Tan, May Ann Lee, Zhiyuan Ke, Babita Madan, David M. Virshup, Li Jun Ding, Vithya Manoharan, Yun Shan Chew, Choon Bing Low, Vishal Pendharkar, Kanda Sangthongpitag, Jeffrey Hill, Thomas H. Keller, and Anders Poulsen. Scaffold Hopping and Optimization of Maleimide Based Porcupine Inhibitors. J. Med. Chem. 2017, 60, 15, 6678–6692.
    • Matthew Ng, David SP Tan, Vivek Subbiah, Colin D. Weekes, Vincenzo Teneggi, Veronica Diermayr, Kantharaj Ethirajulu, Pauline Yeo, Deborah Chen, Stephanie Blanchard, Ranjani Nellore, Bong Hwa Gan, Maryam Yasin, Lay Hoon Lee, May Ann Lee, Jeffrey Hill, Babita Madan, David Virshup, and Alex Matter. First-in-human phase 1 study of ETC-159 an oral PORCN inhibitor in patients with advanced solid tumours. Journal of Clinical Oncology 2017 35:15_suppl, 2584-2584.
    • Ke, Z., Lim, S., Wang, S., Fulwood, J., Proffitt, K., Madan, B., Choong, M., Flotow, H., Virshup, D., Lee, M. Identification of Small Molecule Inhibitors of Wnt Secretion. European Journal of Cancer 2012; Vol. 48, Suppl 6: 52-53.


Target Class Expertise

Our HTS team had worked on a broad range of assays including:

Target Class Signal Transduction/Receptor
Bacterial Phenotypic/Whole Cell Screen Methyltransferase
Bacterial Protease Activator Kinases
Bacterial Protease Inhibitor Bacterial Methyltransferase
Zinc Finger Protein Ion Channel
Gastric Cancer Phenotypic Screen Bacterial Energy Production Pathway
Bacterial Cell Division Protein GPCR
Amino Acid Metabolism/Energy Production Protein Protein Interaction
Signal Transduction Cyclin Dependent Kinase
Viral Target GTPase
Amino Acid Metabolism Viral Methyltransferase

 


Overview of Drug Screening Assays Available with HTS Group

homogenous hts assays

 

Target-based Screening Approaches and Assays Available with HTS Group

target based

 


Key Expertise

  • A team of experienced scientists capable of performing more than 6 HTS campaigns per year in 384 or 1536-well plate formats.
  • HTS workflows are documented with SOPs and Work Instructions to ensure trackability, reliability and reproducibility.

Compound Collections and Management

  • More than 300,000 diverse small molecules meticulously curated by medicinal chemists for drug-likeness and structural diversity with reduced pan-assay interfering (PAINS) and reactive functional groups (REOS). New compounds are filtered to be structurally diverse from existing compounds, hence each acquisition contributes and enhances the diversity of our collections.
  • Collections of focused compound sets for focused screens in specific diseases and protein targets.
  • Quality control of compounds by ultra-high-performance liquid chromatography (UPLC) coupled to mass spectrometry (MS).
  • State-of-the-art automated compound storage facility with temperature & humidity control and compound tracking, sorting and cherry-picking functions.

HTS Automation Platform

  • State-of-the-art customised fully integrated robotic liquid handling platform consisting of >10 instruments controlled by a single master programme to simplify control of these instruments with the aim to increase plate handlings and dispensation throughput.
  • Our unique platform configuration allows for:
    • Assembly and performing automated biochemical screens on up to 16,000 compounds per day.
    • Assembly of up to 50 plates (16,000 compounds) per day for biophysical, cell-based and phenotypic screens conducted at other locations in EDDC.
    • Assembly and cherry picking up to 100 compound plates (32,000 compounds) per day for compound management and Medchem SAR support.
    • Miniaturisation of bioassays for high throughput and cost reduction by reducing typical biochemical screen volumes down to 6-12 µl per well.
    • An in-house developed HTS & compound workflow management programme (PharmApps) that integrates with FDA-compliant HTS data analysis & storage database (IDBS ActivityBase).


Equipment

Fully Integrated Automation Platform

  • Integrated control and scheduling of >10 instruments by one master software.
  • Both nanolitre and microliter dispensing, assay setup, and results reading on a single platform.
  • PharmApps for process & compound usage tracking.
  • FDA compliant data analysis and storage system – ActivityBase.


Our Experts

EARO Scientific Director, Dr. Christophe Bodenreider

Head of HTS, Choong Meng Ling


Publication

HTS (Publications related to screening campaigns & workflow)

  1. Chong DN, Yap A, Goh C, Choong ML, Tan SH. PharmApps: An integrated management application for tracking compound stamping and usage in high throughput screens. Biomed J Sci & Tech Res. 2020; 25(2): 18906-18916.
  2. Zhong W, Koay A, Ngo A, Li Y, Nah Q, Wong YH, Chionh YH, Ng HQ, Koh-Stenta X, Poulsen A, Foo K, McBee M, Choong ML, El Sahili A, Kang C, Matter A, Lescar J, Hill J, Dedon P. Targeting the bacterial epitranscriptome: Discovery of novel tRNA-(N1G37) methyltransferase (TrmD) inhibitors with antibiotic activity. ACS Infectious Diseases. 2019; 5(3): 326-335.
  3. Huang C, Liew S, Lin G, Poulsen A, Ang M, Chia B, Chew S, Kwek Z, Wee J, Ong E, Retna P, Baburajendran N, Li R, Yu W, Koh-Stenta X, Ngo A, Manesh S, Fulwood F, Ke Z, Chung H, Sepramaniam S, Chew X, Dinie N, Lee MA, Chew Y, Low CB, Pendharkar V, Manoharan V, S, Sangthongpitag K, Joy J, Matter A, Hill J, Keller T, Foo K. Discovery of Irreversible Inhibitors Targeting Histone Methyltransferase, SMYD3. ACS Med Chem Lett. 2019; 10(6):978-984.
  4. Shetty A, Xu Z, Lakshmanan U, Hill J, Choong ML, Chng SS, Yamada Y, Poulsen A, Dick T, Gengenbacher M. Novel acetamide indirectly targets mycobacterial transporter MmpL3 by proton motive force disruption. Front. Microbiol. 2018, 9: 2960.
  5. Ngo A, Koay A, Pecquet C, Diaconu CC, Jenkins DA, Shiau AK, Constantinescu SN, Choong ML. Phenotypic screening for inhibitors of a mutant thrombopoietin receptor. In: Wagner B (ed.), Phenotypic Screening: Methods and Protocols. Methods in Molecular Biology. 2018; Vol 1787: 53-66. Humana Press, New York, NY.
  6. Ngo A, Koay A, Pecquet C, Diaconu CC, Ould-Amer Y, Huang Q, Kang C, Poulsen A, Lee MA, Jenkins D, Shiau A, Constantinescu SN, Choong ML. A Phenotypic Screen for Small-Molecule Inhibitors of Constitutively Active Mutant Thrombopoietin Receptor Implicated in Myeloproliferative Neoplasms. Comb. Chem. High T. Scr. 2016; 19: 824-833.
  7. Moreira W, Ngan G, Low JL, Poulsen A, Chia B, Ang M, Yap A, Fulwood J, Lakshmanan U, Lim J, Khoo A, Flotow H, Hill J, Raju R, Rubin EJ, Dick T. Target mechanism-based whole-cell screening identifies bortezomib as an inhibitor of caseinolytic protease in mycobacteria. mBio. 2015 6(3): e00253-15.
  8. Lakshmanan U, Yap A, Fulwood J, Li Y, Sim SH, Lim J, Ting A, Sem XH, Kreisberg JF, Tan P, Tan G, Flotow H. Establishment of a novel whole animal HTS technology platform for melioidosis drug discovery. Comb. Chem. High T. Scr. 2014; 17: 790-803.
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