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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

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    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.

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

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

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    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.

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

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

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    Oncology and Immuno-Oncology

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

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

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  • 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.

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    About Sygnature

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Case Study

Cereblon Crystallography with CRBN-midi: Accelerating Molecular Glue and PROTAC Discovery

Our latest achievement: the successful expression, purification, and crystallization of Cereblon-midi (CRBN-midi) reinforces Sygnature Discovery’s position at the forefront of the rapidly expanding targeted protein degradation (TPD) landscape.

Transforming Drug Discovery

Targeted protein degradation is redefining how scientists approach diseases once considered “undruggable.” Instead of simply blocking the activity of proteins, TPD strategies harness the cell’s own machinery to eliminate them, unlocking new possibilities for next-generation therapeutics.

At the heart of many TPD systems is Cereblon (CRBN), a key component of an E3 ubiquitin ligase complex. Acting as a “molecular matchmaker,” CRBN enables degraders to engage non-native targets effectively by bridging target interactions via PROTACs and molecular glues. However, studying CRBN has been challenging due to its dependence on DDB1 for structural stability. Thanks to the development of the CRBN-midi construct, we can now resolve this challenge with remarkable accuracy and confidence.

The CRBN-Midi Advantage

First introduced by Kroupova et al., the engineered CRBN-midi format preserves CRBN’s functional core while improving stability, solubility, and suitability for structural biology. This construct facilitates X-ray crystallography, enabling structure-based screens and designs for therapeutic applications.

At Sygnature Discovery, we’ve harnessed this design to offer a robust, ready-to-use CRBN-midi system empowering clients to accelerate TPD research with reliable biochemical and biophysical assays. Using the published CRBN-Midi construct, we have enabled an off-the-shelf crystallization system and complementary ligand binding analysis by SPR.

Two Structures, One Breakthrough Platform

Using crystallization conditions similar to those previously reported, followed by X-ray diffraction techniques, we’ve determined high-resolution CRBN-midi structures that can provide valuable insight into CRBN’s binding behavior:

  • Apo CRBN-midi (3.2 Å Resolution): Reveals the apo conformation of CRBN-midi, forming the baseline for ligand-induced structural changes.
  • CRBN-midi–Lenalidomide Complex (1.96 Å Resolution): Highlights molecular interactions critical for degrader design and optimization.
Figure 1: Size exclusion chromatography and SDS-PAGE data showing purity of CRBN-midi
Figure 2. Crystal structures of CRBN-midi in Apo form
Figure 3. a) Crystal structure of CRBN-midi in complex with Lenalidomide
Figure 3. b) Electron density map of Lenalidomide (yellow), 2mFo-DFc map contoured at 1σ, grey

Active and Ready: CRBN-midi Binding Confirmed via SPR

We’ve enabled ligand-binding analysis with CRBN-midi using SPR. Using immobilized CRBN-midi on the sensor surface, we demonstrate saturable binding of lenalidomide.

Figure 4. Binding of lenalidomide to CRBN-midi by SPR: Saturable binding is observed between lenalidomide and immobilized CRBN-midi.

Flexible solutions for degrader design

We now have a complete toolbox to support the design of degraders. The CRBN-midi described here performs well in binary assays, particularly for imids, and is an excellent tool for structure-guided design of new glues and Protacs.  This complements our offer with the full a DDB1/Cereblon complex which performs better in ternary assays, and highlights our deep expertise in the degrader space, delivering high-quality data for complex programs.

Integrated Structural Biology and Biophysical Expertise

Sygnature Discovery offers a fully integrated workflow to support partners at every stage of discovery:

  • Protein Expression and Purification: Optimized systems for challenging targets
  • Compound Screening: To identify binders for molecular glue and PROTAC programs
  • Crystallization and X-ray Structure Determination: Industry-leading resolution and reliability
  • Molecular Glue Characterization: From binding assays to structural and biophysical analysis

Our technical depth, flexibility, and scientific insight deliver structural data that drives informed decisions and accelerates timelines.

Empowering Discovery for Our Partners

Our progress with CRBN-midi does more than deliver faster structural insights, it strengthens CHARMED , Sygnature’s pioneering discovery platform. By integrating these learnings, we expand CHARMED’s ability to accelerate molecular glue and degrader programs for biotech and pharmaceutical innovators.

Contact us today  to learn how our structural biology and ligand screening services can accelerate your next breakthrough.

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