January 9, 2018 | Sage Journals | Agonists and Antagonists of Protease-Activated Receptor 2 Discovered within a DNA-Encoded Chemical Library Using Mutational Stabilization of the Target
The discovery of ligands via affinity-mediated selection of DNA-encoded chemical libraries is driven by the quality and concentration of the protein target. G-protein-coupled receptors (GPCRs) and other membrane-bound targets can be difficult to isolate in their functional state and at high concentrations, and therefore have been challenging for affinity-mediated selection. Here, we report a successful selection campaign against protease-activated receptor 2 (PAR2). Using a thermo-stabilized mutant of PAR2, we conducted affinity selection using our >100-billion-compound DNA-encoded library. We observed a number of putative ligands enriched upon selection, and subsequent cellular profiling revealed these ligands to comprise both agonists and antagonists. The agonist series shared structural similarity with known agonists. The antagonists were shown to bind in a novel allosteric binding site on the PAR2 protein. This report serves to demonstrate that cell-free affinity selection against GPCRs can be achieved with mutant stabilized protein targets.
October 18, 2017|ACS Chemical Biology|Isoform-Selective ATAD2 Chemical Probe with Novel Chemical Structure and Unusual Mode of Action
ATAD2 (ANCCA) is an epigenetic regulator and transcriptional cofactor, whose overexpression has been linked to the progress of various cancer types. Here, we report a DNA-encoded library screen leading to the discovery of BAY-850, a potent and isoform selective inhibitor that specifically induces ATAD2 bromodomain dimerization and prevents interactions with acetylated histones in vitro, as well as with chromatin in cells. These features qualify BAY-850 as a chemical probe to explore ATAD2 biology.
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