X-Chem’s DEL Screening
Finds the Target
There are over 800 G-protein coupled receptors (GPCRs) encoded in the human genome, and approximately half are considered potential targets for drug development. Screening GPCRs in vitro can be challenging due to their complex nature, but X-Chem’s DNA-encoded library (DEL) technology and target class expertise enable successful hit identification where other approaches have failed.
X-Chem’s leading-edge platform enables the screening of vast numbers of compounds, enabling the identification of new chemical matter that can easily be missed using traditional screening techniques. Combining our DEL screening and medicinal chemistry know-how with your in-house expertise is the move that puts your product on the fast track to clinic.
Our Reputation Is Built on Hitting Curveballs
GPCRs modulate a number of cellular processes, and accordingly 33-50% of drugs on the market target this protein class. In spite of this, less than 15% of human GPCRs have been drugged … but
X-Chem is helping to raise that percentage. By overcoming the difficulties of GPCR screening through established methods, X-Chem can drive discovery of GPCR ligands where traditional approaches have proven unsuccessful. For example, in research published from 2017-2020, we worked with our partners (AstraZeneca and Heptares) in efforts to discover PAR2 modulators using mutationally stabilized receptors (StaRs). DEL screening of stabilized PAR2 afforded the identification of both an agonist and an antagonist ligand, demonstrating the robustness of our technology. These efforts have illuminated distinct mechanisms of inhibition, as well as strategies of investigation in underexplored areas. This is just one example of how X-Chem’s experience, DEL screening capabilities and collaborative commitment are driving GPCR discovery efforts.
Screening in Lysate
Despite a number of available methods to allow successful screening of recombinant GPCRs, sometimes a target will require a true cellular environment for proper structure and function. For these situations, X-Chem has developed a lysate screening approach, where we can screen directly from the cellular milieu, ensuring that a target is properly folded, functional and engaged with relevant binding partners. The results of this technique are summarized in the figure below. Lysate screening enables the identification of active compounds which would have otherwise gone undetected by traditional DEL screening methods.
Your Partner for Challenging Targets
With robust process and a partner-first approach to the most difficult classes, we put your toughest target in range. Put our industry-leading DEL platform and medicinal chemistry expertise to work for you and find new possibilities for your GPCR discovery program.