April 26, 2017|Nature|Structural insight into allosteric modulation of protease-activated receptor 2
Protease-activated receptors (PARs) are a family of G-protein-coupled receptors (GPCRs) that are irreversibly activated by proteolytic cleavage of the N terminus, which unmasks a tethered peptide ligand that binds and activates the transmembrane receptor domain, eliciting a cellular cascade in response to inflammatory signals and other stimuli. PARs are implicated in a wide range of diseases, such as cancer and inflammation1, 2, 3. PARs have been the subject of major pharmaceutical research efforts3 but the discovery of small-molecule antagonists that effectively bind them has proved challenging.
2017 Jan. 5|Chembiochem.|Discovery of a potent BTK inhibitor with a novel binding mode using parallel selections with a DNA-encoded chemical library.
We have identified and characterized novel potent inhibitors of Bruton’s tyrosine kinase (BTK) from a single DNA encoded library of over 110 million compounds using multiple parallel selection conditions…Analysis of the co-crystal structure of the most potent compound demonstrates a novel binding mode that reveals a new pocket in BTK. Our results demonstrate that profile-based selection strategies form the basis of a new methodology to rapidly identify small molecule inhibitors with novel binding modes to clinically relevant targets using DNA-encoded libraries.
Dec 9, 2016|Nat Rev Drug Discov.|DNA-encoded chemistry: enabling the deeper sampling of chemical space.
DNA-encoded chemical library technologies are increasingly being adopted in drug discovery for hit and lead generation…This Review provides an overview of the development and applications of DNA-encoded chemistry, highlighting the challenges and future directions for the use of this technology.
Nov. 18, 2016|Proc Natl Acad Sci U S A.|Discovery of cofactor-specific, bactericidal Mycobacterium tuberculosis InhA inhibitors using DNA-encoded library technology.
Millions of individuals are infected with and die from tuberculosis (TB) each year, and multidrug-resistant (MDR) strains of TB are increasingly prevalent…We describe here the use of DNA-encoded X-Chem (DEX) screening, combined with selection of appropriate physical properties, to identify multiple classes of InhA inhibitors with cell-based activity…
JULY 13, 2016|BIOWORLD TODAY|”‘X-Chem’ Marks the Spot for Bayer in Sweetened Drug Discovery Deal”
Bayer AG and privately held X-Chem Inc. expanded their global drug discovery collaboration, initiated in 2012, to encompass the entire bandwidth of therapeutic areas and target classes from Bayer’s R&D pipeline.
Jun 10, 2015|Sci. Rep.|Encoded Library Synthesis Using Chemical Ligation and the Discovery of sEH Inhibitors from a 334-Million Member Library.
A chemical ligation method for construction of DNA-encoded small-molecule libraries has been developed. Taking advantage of the ability of the Klenow fragment of DNA polymerase to accept templates with triazole linkages in place of phosphodiesters, we have designed a strategy for chemically ligating oligonucleotide tags using cycloaddition chemistry. We have utilized this strategy in the construction and selection of a small molecule library, and successfully identified inhibitors of the enzyme soluble epoxide hydrolase.
June 2015|Curr Opin Chem Biol.|Chemical ligation methods for the tagging of DNA-encoded chemical libraries.
The generation of DNA-encoded chemical libraries requires the unimolecular association of multiple encoding oligonucleotides with encoded chemical entities during combinatorial synthesis processes. This has traditionally been achieved using enzymatic ligation. We discuss a range of chemical ligation methods that provide alternatives to enzymatic ligation.
March 31, 2014 | CEOCFO | “Discovering Small Molecule Compounds through The DNA Encoded Library Technology”
Interview with Richard W. Wagner, CEO, X-Chem
February 24, 2014 | BioCentury | “Bigger is Better”
“The vision is that when the library is big enough, molecules that are practically drug candidates will emerge from the primary screen.”
February 13, 2014 | Journal of Biomolecular Screening | “Overview of Recent Progress in Protein-Expression Technologies for Small-Molecule Screening”
Production of novel soluble and membrane-localized protein targets for functional and affinity-based screening has often been limited by the inability of traditional protein-expression systems to generate recombinant proteins that have properties similar to those of their endogenous counterparts.