PROTACs
Unlocking undruggable targets with targeted protein degradation
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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 is a lack of available clinical therapies to modulate the activity of such targets. PROteolysis TArgeting Chimeras (PROTACs®) have emerged as revolutionary tools to address this unmet need. Unlike traditional small molecules which only transiently modulate the activity of biological targets, PROTACs mediate the formation of a ternary complex including E3 ubiquitin ligases and the protein of interest, triggering its proteosome-mediated degradation. This unique chemical knock-down approach not only provides a new paradigm to drug the human proteome, but also furnishes valuable tool compounds for validating new and emerging biological targets.
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A more in-depth view
Challenges in PROTAC development and characterisation
Despite their promises, PROTACs also present several challenges. These include:
- Solubility: Due to their large size and hydrophobic nature, PROTACs typically have low aqueous solubility and are prone to aggregation. This often leads to low oral bioavailability, posing a significant challenge for PROTAC development.
- Assessing complex formation: Successful binary and ternary complex formation is critical for protein degradation. Optimising the binding affinity and kinetics of each ligand to ensure a controlled and efficient assembly of both complexes is also key for assessing delivery and uptake, as well as for the efficiency and specificity of the ubiquitination process.
- Delivery and cellular uptake: Efficient delivery of PROTACs to the target cells and tissues is challenging partially due to their complex structures and physicochemical properties. Achieving effective cell uptake while maintaining stability is essential for therapeutic success.
- Selectivity and specificity: Engineering optimal selectivity for the protein of interest in the intended cellular context while minimising off-target effects is crucial.
- Protein degradation kinetics: Achieving the desired balance between efficient protein degradation while avoiding excessive degradation that might lead to toxicity or unintended consequences is important for optimisation.
- In vivo stability: PROTACs need to remain stable in the intricate in vivo environment to elicit their therapeutic effects, but rapid degradation or modification of PROTACs in this environment can limit their efficacy. Therefore, assessing PROTAC stability in early stages of development can help to address this risk and improve PROTAC performance.
Solutions to these complex challenges
Our team of medicinal, synthetic, and computational chemists, ADME scientists and biologists offer a range of services designed to help you overcome challenges specific to your PROTAC development program:
- Our chemists have significant experience of working with Cereblon, VHL, and IAP-based PROTACs and have established a library of linkers available in-house, along with the knowledge and expertise on linker design and synthesis to accelerate your PROTAC program.
- We utilize state-of-the-art technologies that enable real-time characterisation of both PROTAC efficacy and mechanism of action, addressing key questions to accelerate PROTAC development, profiling, and guidance on chemical structure−activity relationships.
- Our customers are given direct access to a multidisciplinary team of expert scientists with unequalled experience working within PROTAC development programs – meaning they can help you overcome specific challenges and identify the right technology for your projects
Computational modelling to gain mechanistic insights
Computational modelling of your protein of interest, PROTAC, and E3 ligase can facilitate the design of the best vectors and linker lengths. With state-of-the-art modelling software, we can provide structure-based drug design (SBDD) support to fashion and prioritize the best PROTAC design ideas.
Tailored PROTAC characterisation workflows
Our team of expert biologists create an integrated in vitro characterisation workflow adapted to your PROTAC molecules using a variety of biophysical and cell-based assays. Our bespoke assays allow you to:
- Optimise PROTAC stability, solubility, and formulation by assessing physiochemical characteristics using Differential Scanning Calorimetry (DSC) [ZN1] and Dynamic Light Scattering (DLS)
- Analyse the affinity, kinetics, and thermodynamics of binary and ternary complex formation using a variety of label-free technologies, including Grating Coupled Interferometry (GCI), Surface Plasmon Resonance (SPR), Differential Scanning Fluorimetry (DSF), and Isothermal Titration Calorimetry (ITC).
- Determine PROTAC 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,[ZN3] respectively.
Bespoke ADMET screening
Concept Life Sciences offers a range of in vitro and in vivo ADMET services, delivering high quality, accurate, and reproducible data.
In addition to our core service of validated robust assays, we can modify and/or customize your assay design, ensuring a science-led, flexible, and quality-driven approach which is important for atypical molecules such as PROTACs.
We will help you make technical choices or strategic decisions on test compound characterization, SAR generation, and optimisation of compound design, supporting you in de-risking your best route to clinic.
