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PROTACs and molecular glues

Unlocking Previously Undruggable Targets

While advances in drug discovery and precision medicine have paved the way for innovative therapeutic development, most of the human proteome, including several important oncoproteins, transcription factors, and non-enzymatic proteins, remain undruggable. This is often due to a lack of deep binding pockets for small molecules to interact with, undesirable off-target effects, and/or large protein-protein interaction interfaces. As a result, despite their disease burden there are a lack of available clinical therapies to modulate the activity of such targets. PROteolysis TArgeting Chimeras (PROTACs®) and molecular glues have emerged as revolutionary tools to address this unmet need by proximity induced targeted protein degradation rather than small molecule inhibition.

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A more in-depth view

Targeted protein degradation

Unlike traditional small molecules which only transiently modulate the activity of biological targets, PROTACs are heterobifunctional molecules connected by a linker, with one moiety targeting an E3 ligase and the other, the protein of interest (POI). Binding of the PROTAC to both targets induces the formation of a ternary complex, which triggers proteosome-mediated degradation of the POI. In contrast, molecular glues are small molecules that act as a bridge to bind both the E3 ligase and the POI to also mediate proximity-induced degradation. These unique chemical knock-down approaches not only provide a new paradigm to drug the human proteome, but also furnish valuable tool compounds for validating new and emerging biological targets.

Challenges in degrader development and characterisation

Despite their promise, PROTACs and molecular glues also present several challenges, but our team of medicinal, synthetic, and computational chemists, ADME scientists, and biologists offer a range of custom services designed to help you overcome challenges that are specific to your degrader development program (Table 1).

We utilise state-of-the-art technologies that enable real-time characterisation of both degrader efficacy and mechanism of action, addressing key questions to accelerate PROTAC or molecular glue development, profiling, and guidance on chemical structure−activity relationships.

Our clients are given direct access to a multidisciplinary team of expert scientists with unequalled experience working within degrader development programs – meaning they can help you overcome specific challenges and identify the right technology for your projects.

A tailored degrader characterisation workflow

  • Use a structure- and/or ligand-based approach to design and synthesize degraders against your preferred ligase and POI with our expert team of medicinal and computational chemists.
  •  Optimise degrader stability, solubility, and formulation by assessing physiochemical characteristics along with ADME and DMPK characteristics, which can also be informed by in silico modelling.
  • Analyse the affinity, kinetics, and thermodynamics of binary and ternary complex formation using a variety of label-free technologies, including GCI, SPR, ITC.
  • Determine intracellular target engagement and degradation kinetics in a variety of cell lines using cell-based assays which are relevant to your disease model and project aims.
  • Gain insights into the phenotypic effects of protein degradation in cells and tissues using live cell imaging and tissue staining, respectively

In addition to our core multi-disciplinary service of validated robust assays, we can modify and/or customise your assay design, ensuring a science-led, flexible, and quality-driven approach which is important for atypical molecules like PROTACs and molecular glues. We can help you make technical choices or strategic decisions on degrader characterisation, SAR generation, and optimisation of compound design, supporting you in de-risking your best route to clinic.