TECHNOLOGIES & PLATFORMS

HIGH THROUGHPUT SCREENING

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We support small molecule drug discovery projects at EDDC with the primary goals of identifying high quality hit compounds that have novel molecular structures and to supply directions for their optimisation.

CAPABILITIES

  • A team of experienced scientists.
  • 10 HTS campaigns per year (384 or 1536-well plate formats)
  • A library of 500,000 unique small molecules with emphasis on structural diversities and reduced PAINS.
  • State of the art automated compound storage facility and a fully integrated robotic liquid handling platform capable of nanolitre liquid dispensing.
  • A HTS workflow management software (PharmApps) that integrates with FDA-approved commercial HTS data analysis software.
  • Miniaturise and optimise bioassays to rapidly screen large numbers of diverse small molecules to identify active compounds.
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IN VITRO BIOLOGY

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We support the discovery of new drugs, both small molecules and biologics, across a broad range of therapeutic areas. We develop biochemical assays for characterising enzyme kinetics, determining mechanism of inhibition and evaluating the binding properties of a molecule to its target using biophysical tools.

CAPABILITIES

  • Optimise purification methods to generate recombinant proteins in a homogenous and active state to be used for early drug discovery studies, including target validation, enzyme characterisation, Fragment Based Screening (FBS) and High Throughput Screening (HTS).
  • State of the art instrumentation enables the development of robust end point and kinetic biochemical assays for multiple target classes. The detection methods include Fluorescence (FP, FI, TR-FRET, ALPHA, LANCE), Luminescence (Luciferase), Absorbance (UV/VIS) and direct measurement using MS.
  • In-house biophysics platform (SPR, ITC and Thermal shift assays) for the determination of kinetics, affinity and thermodynamic binding parameters of small molecules, peptides and protein-protein interactions.
  • For anti-bacterial projects, we perform antimicrobial susceptibility testing (MIC, MBC determination), mode of action (cidal, static), time kill kinetics assay and antimicrobial drug-drug interactions (synergism, antagonism) for a range of pathogenic organisms.
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CELL-BASED ASSAY DEVELOPMENT

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Cell-based assays are critical for drug discovery. The effects of new drugs on different cell types are usually studied using continuous cell lines.

We have developed cell reporter assays and cytotoxic assays such as apoptosis, cell proliferation, soft agar colony formation and metabolic assays. By engineering cells to produce suitable markers for a particular pathway, we develop selectivity assays for identified hits and to probe the mechanisms of action. Examples of these assays are receptor binding, receptor activation, cell signaling, sub-cellular localisation as well as specific gene knockout and knockdown cells. Suitable biomarkers are also identified for use in the development of preclinical development candidates.

Different readout and detection format of assays such as luminescence, fluorescence and imaging are available which can be optimised and miniaturised for High Throughput Screening. We can also develop assays to screen and select for specific and potent derivatives of hits in a panel of cancer cell lines and normal cells.

APPLICATIONS

Compound screening, confirmation of hits in cell lines and supporting lead optimisation for drug discovery.

EQUIPMENT

  • Bravo robotic liquid handler
  • Infinite M200Pro microplate reader with injector
  • FACSArray 96-well plate flow cytometer
  • xCelligence real-time cell analyzer
  • NanoPro 100 System for quantitative immunoassay
  • Gelcount tumour colony counter
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STRUCTURAL BIOLOGY

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Our structural biology platform supports target-based drug discovery projects at EDDC. X-ray crystallography and NMR spectroscopy techniques are utilized to determine high-resolution structures of proteins and ligand binding conformations. Understanding protein-ligand interactions is pivotal for accelerating lead identification and structure guided lead optimisation.

CAPABILITIES

  • Nano volume crystallization using high throughput liquid handling platform
  • Access to both in-house X-ray diffractometer and international synchrotrons for data collection, access to state of the art NMR instrumentation (400 to 800MHz)
  • Capability in rational drug design and solving novel protein structures
  • Analyzing protein dynamics, protein-protein interactions and structure-activity relationships (SAR) using NMR
  • Application of Saturation-Transfer Difference (STD), WaterLOGSY experiments and 19F-NMR to screen novel fragments to support fragment-based discovery projects.
  • Application of protein-observed NMR techniques to determine ligand binding modes and perform target engagement under physiological conditions.
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DISCOVERY CHEMISTRY

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Our science is focused on studying the interaction of small molecular weight compounds with biomacromolecules. Through the application of cutting edge technologies, we aim to deliver tool compounds for target validation and optimised drug candidates to treat patients.

FRAGMENT BASED SCREENING

Using biophysical screening methods, we elucidate high quality chemical starting points for hit-to-lead optimisations. The screening of a proprietary library and high throughput chemistry infrastructure enables us to efficiently optimise a fragment hit. Work done in this area is highly multidisciplinary and spans the use of chemistry, structure biology and biophysics to rapidly advance projects.

MEDICINAL CHEMISTRY

The medicinal chemistry group generates drug candidates from fragments or screening hits, through a multidimensional, iterative design process involving multiple chemists, biologist and pharmacologists.

PEPTIDE CHEMISTRY

Are you working on a peptide with biological properties? We can help you design, modify and drive your peptide into clinical development!

CHEMICAL BIOLOGY AND NEW CHEMICAL TECHNOLOGIES

Our team is constantly investing in technologies that have the potential to accelerate or disrupt the drug discovery processes.

  • Application of Artificial IntelligenceMachine learning holds great promise in revolutionizing the pharmaceutical industry. We are collaborating with industry partners and other A*STAR research institutes to apply Deep Learning in our lead optimisation campaigns.
  • Protein Degradation technologiesThe use of small molecule probes to elucidate disease-associated biological phenomena is a powerful approach in target validation. Targeted protein degradation is one promising technique for augmenting current target validation strategies.
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ANTIBODY BIOLOGY

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We leverage on single B cell technology, along with an automated workflow, to deliver successful biotherapeutics projects. Our team consists of highly skilled scientists with a wealth of experience in High-Throughput hits-to-lead identification, antibody purification and characterisation.

Lead antibody candidates with desired biological activity will undergo robust assessments (affinity, epitope binning, EC50 and IC50, cross-species reactivity and developability) and optimisation (Fc engineering and affinity maturation).

CAPABILITIES

  • High-Throughput Animal B cell Cloning
  • Next-generation Human B cell Cloning
  • Automated Workflow
  • Antibody/Antigen Production
  • Antibody Screening and Characterisation
  • Antibody Engineering for Lead Optimisation
  • Developability Assessment
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DISCOVERY & PRECLINICAL SCIENCES

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We help assess drug metabolism, pharmacokinetic properties (DMPK) and animal pharmacology of your lead molecules. Once a molecule is selected for development, investigational new drug (IND) enabling activities are conducted before regulatory submission and approval prior to human clinical trials.

ANIMAL PHARMACOLOGY

  • Develop animal models for efficacy testing. Efficacy of candidate molecules in disease models are essential to support clinical efficacy assessment in humans

DRUG METABOLISM AND PHARMACOKINETICS (DMPK)

  • P450 metabolism, pasma protein binding
  • Examining the concentration and changes of the compound once administered into animals
  • Pharmacokinetic-pharmacodynamics (PKPD) assessments
  • Predict DMPK in humans

CHEMISTRY, MANUFACTURING AND CONTROL (CMC)

  • cGMP manufacturing of the drug substance and drug product, with the quality acceptable to regulatory authorities for testing in animals and humans

GLP TOXICOLOGY

  • Testing of drug candidates for safety pharmacology and general toxicity. Information helps to determine the safe starting dose and identify parameters for monitoring safety in humans
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THERAPEUTICS DEVELOPMENT

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We bring your drug/device from conception to the clinic! We have proven capabilities in the following areas:

  • Biomarker Guided Clinical Trials
  • Clinical Development from first-in-human to proof-of-concept clinical trials, and beyond

BIOMARKER GUIDED CLINICAL TRIALS

PHARMACODYNAMIC (PD) BIOMARKERS

Our oncology programmes use PD biomarkers to show that the drug hits its target, and to guide preclinical and clinical development.

Assays to analyse these markers are established and analytically validated, and are performed under standardised conditions. Data obtained from correlations between drug concentrations in blood/tissue and the extent of effect observed on the PD marker may enable determination of a Proof-of-Mechanism (PoM). Data is also used to inform pharmacological modelling, to guide dosing schedules, to determine a biologically active dose, or for estimation of the therapeutic index of a drug.

Examples of this can be found in the following clinical studies:

PATIENT SELECTION BIOMARKERS

Whenever possible we utilise patient selection biomarkers in our clinical trials to maximise the benefit of a specific patient population from treatment.

CASE STUDY – RSPO FUSION TEST KIT / ETC-159

Colorectal cancer (CRC) patients with four different recurrent RSPO gene fusions are predicted to benefit from the treatment with ETC-159, which was also shown in preclinical mouse models.

A test for this positive predictive biomarker was developed to screen for these patients (D3 RSPO Fusion Test Kit) for inclusion in the Phase 1B trial of ETC-159 (NCT02521844). The test is currently being offered as a laboratory developed test by our collaborators, POLARIS @ GIS

CLINICAL DEVELOPMENT

The evaluation of the safety and efficacy of new pharmaceutical products in humans is a fundamental step towards bringing new medicines to Singapore and the world. Clinical development ensures this through the conduct of early clinical trials in healthy volunteers and patients. These are often referred to as first-in-human (FIH), first-in-disease (FID) and/or proof-of-concept (PoC) studies. Results from these studies determine the progression of a drug through clinical development and are necessary for marketing approval of a new drug by regulatory authorities.

We uphold international ethical and scientific quality standards when performing these clinical trials. With volunteer and patient safety our highest priority, we strictly adhere to both global and local rules governing investigations involving human subjects. Our studies are conceived, designed and implemented to the highest standards of science and methodology, and are based on best practices.

Our clinical trials foster innovation and advance therapeutics development, sharing knowledge and creating partnerships with leading scientific and medical professionals around the world.

Compounds we have brought into clinical development include:

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