Science and Technology
December 5, 2014

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Publications

January 5, 2017

Discovery of a potent BTK inhibitor with a novel binding mode using parallel selections with a DNA-encoded chemical library.

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.

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December 9, 2016

DNA-encoded chemistry: enabling the deeper sampling of chemical space.

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.

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November 18, 2016

Discovery of cofactor-specific, bactericidal Mycobacterium tuberculosis InhA inhibitors using DNA-encoded library 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…

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June 10, 2015

Encoded Library Synthesis Using Chemical Ligation and the Discovery of sEH Inhibitors from a 334-Million Member Library.

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.

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June 1, 2015

Chemical ligation methods for the tagging of DNA-encoded chemical libraries.

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.

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February 24, 2014

Bigger is Better

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.”

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February 13, 2014

Overview of Recent Progress in Protein-Expression Technologies for Small-Molecule Screening

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.

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January 31, 2014

Universal strategies for the DNA-encoding of libraries of small molecules using the chemical ligation of oligonucleotide tags

January 31, 2014 | Taylor Francis Online | “Universal strategies for the DNA-encoding of libraries of small molecules using the chemical ligation of oligonucleotide tags”

The affinity-mediated selection of large libraries of DNA-encoded small molecules is increasingly being used to initiate drug discovery programs.

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