X-Chem, Inc. and AstraZeneca have been collaborating since 2012 to discover new chemical starting points against very challenging drug targets. A central part of the collaboration has been to screen these targets using X-Chem’s DNA encoded library of over 100 billion molecules. Based on initial success from the first few screens that were conducted, the collaboration was further expanded in 2013 to encompass a broad range of drug targets across therapeutic areas.
The X-Chem drug discovery engine is based on a library generated by iterative combinatorial synthesis of small molecules tethered to DNA tags that record the synthetic history of the small molecule. Every small molecule in the library has a unique DNA barcode attached to it. The library is screened as a mixture using affinity-based binding to a target of interest. Certain rare molecules in the library that bind to the target can be “fished out,” while the rest of the molecules wash away. DNA sequencing methods are then used to detect molecules that are enriched when bound to the target. The diverse nature of the library produces multiple families or clusters of related molecules that bind to the target, forming a basis for emergent structure-activity relationships. Structure-activity relationships are typically used by medicinal chemists to guide iterative chemical maturation of a molecule into a drug. Based on the synthetic history encoded in the DNA sequence information, molecules are then made without the DNA tag attached, and tested for activity in conventional assays.
Due to the size and diversity of the library, X-Chem and AstraZeneca scientists have discovered multiple series of novel, potent and selective lead compounds against a wide range of targets, including some that previously failed using conventional screening methods. One particular example is a very challenging GPCR that is being researched at AstraZeneca for neuropathic pain and inflammation. Following the X-Chem screen, several series of cellular active molecules were identified with high potency. Three of the series were antagonists of the GPCR, and an additional series, interestingly, produced agonists. AstraZeneca licensed the program, and collaborative work is actively underway.
The X-Chem/AstraZeneca alliance has grown dramatically, encompassing over 50 drug targets, 7 licensed programs (so far), and the production of exclusive DNA encoded libraries that were designed by AstraZeneca chemists incorporating AZ proprietary chemical building blocks. Success has been demonstrated against targets involved in the lipid biosynthesis pathways of gram negative bacteria, a tuberculosis target, protein:protein interaction (PPI) targets, kinases, GPCR’s, and E3 ligases to name a few. Success like this only comes from the high level of collaboration and interaction between the AZ and X-Chem scientists, along with strong leadership between the companies who rapidly identify issues and work towards mutually beneficial solutions. X-Chem looks forward to ongoing interaction and deeper utilization of the DNA encoded library platform as one of the pillars of AZ’s discovery efforts.