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  • Integrated Drug Discovery

    Integrated Drug Discovery

    Overview

    We deliver truly integrated drug discovery programs. Our co-located teams accelerate compounds from target ID to candidate.

  • Target Identification & Validation

    Target Identification & Validation

    It’s important to lay strong foundations for successful drug discovery at this first stage of the process. Our integrated target identification and validation platform combines AI with expert insights, and rigorous lab validation to guide targets through robust evaluation, ready for hit discovery.

  • Hit Identification

    Hit Identification

    Validated, high-quality hits, delivered through integrated technologies and expert collaboration, give you a confident starting point for faster drug discovery.

  • Hit-to-Lead

    Hit-to-Lead

    High-quality hits with early proof of concept are de-risked and profiled, ready to accelerate your program towards lead optimization.

  • Lead Optimization

    Lead Optimization

    Turning promising leads into clinical candidates with speed, precision, and the scientific expertise to generate high-quality data and deliver real patient impact.

Featured Resources

  • Modalities

    Modalities

    Overview

    Delivering integrated, modality-agnostic drug discovery to tackle complex biology, accelerate development, and advance innovative therapies with confidence.

  • Small Molecules

    Small Molecules

    Expert small molecule discovery from target ID to scale-up, delivering candidates designed for success and market impact.

  • Peptides

    Peptides

    Transforming complex peptide concepts into next-generation therapies through integrated design, advanced analytics, and collaborative end-to-end discovery expertise.

  • Targeted protein degradation

    Targeted protein degradation

    Leveraging induced proximity and CHARMED technology to rapidly design, test, and optimize degraders for previously ‘undruggable’ targets.

  • ADCs

    ADCs

    Advancing next-generation ADCs through payload-focused design, integrated expertise, and collaborative innovation to deliver safer, more selective therapies.

  • Biologics

    Biologics

    Driving biologics innovation through integrated design, structural biology, and multidisciplinary expertise to accelerate next-generation therapies from concept to clinic.

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  • Therapeutic Areas

    Therapeutic Areas

    Overview

    Combining deep therapeutic expertise with translational insight to design strategies, reduce risk, and accelerate discovery programs toward clinical success.

  • Oncology and Immuno-Oncology

    Oncology and Immuno-Oncology

    Accelerating oncology drug discovery through integrated expertise, innovative modalities, and translational insight to deliver candidates with real clinical impact.

  • Inflammation and Immunology

    Inflammation and Immunology

    Driving immunology and inflammation drug discovery through tailored assays, translational models, and integrated expertise for faster clinical success.

  • Neuroscience

    Neuroscience

    Advancing CNS drug discovery through integrated models, translational biomarkers, and multidisciplinary expertise to overcome complexity and accelerate therapeutic innovation.

  • Metabolic Diseases

    Metabolic Diseases

    Designing and advancing differentiated small-molecule therapies for obesity and diabetes through integrated expertise, mechanistic insight, and translational strategies.

Featured Resources

  • CellCentric Lead Optimisation Campaign - CCS1477

    CellCentric Lead Optimisation Campaign - CCS1477

    Inobrodib, an exciting, first-in-class oral anti-cancer drug in clinical development by CellCentric, was collaboratively designed, synthesised and supported on its pre-clinical journey by an integrated project team at Sygnature Discovery. Inobrodib is now showing promising results in Phase I and II trials for multiple myeloma and other cancer types.

    Case study
  • About Sygnature

    About Sygnature

    At Sygnature Discovery, we deliver world-leading drug discovery solutions to accelerate your compound from idea to clinic.

  • Meet our Team

    Meet our Team

    Our leadership team brings diverse experience and insight, driving collaboration and innovation across drug discovery.

  • Careers

    Careers

    Explore careers at Sygnature Discovery and join a global team committed to science, collaboration, and integrity.

Technical Notes

Microsomal Stability

About the Assay

Sygnature Discovery’s microsomal metabolic stability assay provides a robust in vitro system for assessing the intrinsic clearance (CLint) of drug compounds using liver microsomes from multiple preclinical species and human donors. Liver microsomes contain a subset of phase I and phase II drug‑metabolising enzymes, predominantly cytochrome P450 isoforms and associated oxidative pathways, offering a mechanistically relevant model for evaluating metabolic turnover. By monitoring parent compound depletion over time, the assay quantifies microsomal stability and supports prediction of in vivo clearance using established scaling factors.

This validation included human, mouse, rat, dog and monkey microsomes, selected to represent a broad range of metabolic capabilities and clearance mechanisms. Human microsomes were prepared from pooled donors to minimise inter‑individual variability, while animal microsomes were pooled to ensure representative species performance. A diverse panel of probe substrates spanning CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5 pathways were incorporated to challenge the system and verify metabolic competence. Assays were run on a Beckman Biomek i5‑MC automated liquid‑handling platform.

The study successfully demonstrated that the microsomal stability assay provides robust, reproducible metabolic intrinsic clearance data suitable for early‑stage optimisation, compound selection and cross-species comparison in drug discovery programs.

Protocol Summary

The microsomal metabolic stability assay evaluates compound turnover by incubating test compounds with pooled liver microsomes and quantifies parent depletion over a series of time points. Test compounds are first prepared from concentrated DMSO stock solutions and combined with microsomes for a short pre‑incubation period. The metabolic reaction is then initiated by addition of co-factor. At predetermined time points, aliquots are removed and quenched to terminate metabolic activity, generating a time course of compound disappearance.

Following centrifugation to remove precipitated proteins, supernatants are pooled for cassette analysis and diluted with water containing internal standard. Samples are analysed via LC–MS/MS to determine the percentage parent compound remaining at each time point. Natural log transformation of compound response–time data enables linear regression to derive the elimination rate constant (k), from which half‑life and intrinsic clearance values are calculated.

The workflow supports high‑throughput automation and ensures excellent reproducibility across assays. The use of pooled microsomes reduces biological variability, while inclusion of a minus‑cofactor control enables differentiation of cofactor‑independent metabolic pathways.

Validation Results

Validation demonstrated that the microsomal stability assay delivers reliable, reproducible CLint values across species.

The graph below presents the validated inter‑assay performance for human liver microsomes. Data represent mean values ± SD.

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