PROTACs are providing a different way to modulate and treat a wide range of diseases through their ability to target protein degradation. A number of new players are actively engaged in harnessing the potential of PROTACs to create therapeutics with enhanced specificity and efficacy. This is helping to increase the tractability of previously challenging drug discovery targets.

PROTACs generally sit outside Lipinski space, their mechanism of action requiring larger molecular weights and distinct physicochemical properties (beyond the Rule of Five, Ro5). While these characteristics hold promise for novel drug modalities, they present challenges, particularly in terms of permeability and bioavailability. Having the ability to understand molecular profiles and characteristics as quickly and efficiently as possible is key to supporting profile improvement/optimisation to reach candidate profiles as rapidly as possible.

Unveiling the ChameLogK Assay for Enhanced Drug Discovery

As we navigate the complexities of PROTAC molecule design, drawing from historical perspectives and contemporary advancements will contribute to a more comprehensive understanding and facilitate the development of optimized and effective therapeutics.

In this regard, chameleonicity, denoting a molecule's ability to adapt to its environment through conformational changes, presents a strategic approach in medicinal chemistry. The optimization of solubility and permeability through the design of molecular chameleons is a key focus in this strategy.  

The ChameLogK paper unveils a descriptor of chameleonicity, demonstrating its effectiveness in evaluating 55 compounds, including those falling within or beyond Rule of Five (Ro5) boundaries. The paper showcases the assay's utility in combination with lipophilicity (BRlogD) and polarity (Δ log kwIAM) descriptors, providing a comprehensive understanding of a compound's profile. The inclusion of selected case studies, covering macrocycles, non-macrocyclic compounds, and PROTACs, further highlights the assay's versatility and its role in property-based drug discovery strategies for designing bioavailable compounds beyond Ro5 constraints.

o2h discovery is proud to disseminate the ChameLogK assay - a groundbreaking, and cost-effective method for measuring chameleonicity, a vital factor in assessing PROTAC molecules' potential. The assay, detailed in a paper accessible here (ChemlogK paper), offers a novel chromatographic descriptor with clear applications in drug discovery. 

We not only endorse the ChameLogK assay's capabilities but have also validated its results at our end. This validation not only underscores the reliability of the assay but also demonstrates our dedication to providing our clients with trustworthy and impactful solutions.

In our comprehensive assay validation, PROTACs displayed a distinct "Chameleonic" quality. Macrocycles, led by Cyclosporin, demonstrated variable behavior, while small molecules surprised with unexpected aggregation tendencies. E3 ligands exhibited consistent behavior, possibly involving internal folding or interactions. Surprisingly, molecules like acetone, caffeine, and diazepam defied expectations. Phenol, despite its rigidity, showed a reproducible profile.

o2h discovery; First in the World to Offer the ChameLogK Assay to our Clients…

Our off-the-shelf-Toolbox for PROTAC Synthesis

To know more about E3 ligase and linkers from our off-the-shelf-toolbox, or to talk to our expert to discuss your PROTAC programme, please reach out to us at discovery@o2h.com