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PROTACs

Unlocking undruggable targets with targeted protein degradation

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.