title: Discovering Drugs with DNA-Encoded Library Technology: From Concept to Clinic with an Inhibitor of Soluble Epoxide Hydrolase.
abstract: DNA-encoded chemical library technology was developed with the vision of its becoming a transformational platform for drug discovery. The hope was that a new paradigm for the discovery of low-molecular-weight drugs would be enabled by combining the vast molecular diversity achievable with combinatorial chemistry, the information-encoding attributes of DNA, the power of molecular biology, and a streamlined selection-based discovery process. Here, we describe the discovery and early clinical development of GSK2256294, an inhibitor of soluble epoxide hydrolase (sEH, EPHX2), by using encoded-library technology (ELT). GSK2256294 is an orally bioavailable, potent and selective inhibitor of sEH that has a long half life and produced no serious adverse events in a first-time-in-human clinical study. To our knowledge, GSK2256294 is the first molecule discovered from this technology to enter human clinical testing and represents a realization of the vision that DNA-encoded chemical library technology can efficiently yield molecules with favorable properties that can be readily progressed into high-quality drugs.
authors.affiliation: GlaxoSmithKline R&D, 830 Winter Street, Waltham, MA, 02451, USA.
authors.forename: Svetlana L
authors.initials: SL
authors.lastname: Belyanskaya
authors.affiliation: GlaxoSmithKline R&D, 830 Winter Street, Waltham, MA, 02451, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Ding
authors.affiliation: GlaxoSmithKline R&D, 709 Swedeland Road, King of Prussia, PA, 19406, USA.
authors.forename: James F
authors.initials: JF
authors.lastname: Callahan
authors.affiliation: GlaxoSmithKline R&D, 709 Swedeland Road, King of Prussia, PA, 19406, USA.
authors.forename: Aili L
authors.initials: AL
authors.lastname: Lazaar
authors.affiliation: GlaxoSmithKline R&D, 830 Winter Street, Waltham, MA, 02451, USA.
authors.forename: David I
authors.initials: DI
authors.lastname: Israel
mesh_terms: D002986:Clinical Trials as Topic; D020650:Combinatorial Chemistry Techniques; D003514:Cyclohexylamines / Q000737:chemistry / Q000493:pharmacokinetics; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D055808:Drug Discovery; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006207:Half-Life; D006801:Humans; D008024:Ligands; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D054852:Small Molecule Libraries / Q000737:chemistry*; D014227:Triazines / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D003514:Cyclohexylamines; D008024:Ligands; C584201:N-((4-cyano-2-(trifluoromethyl)phenyl)methyl)-3-((4-methyl-6-(methylamino)-1,3,5-triazin-2-yl)amino)cyclohexanecarboxamide; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; D014227:Triazines; D004247:DNA; D004851:Epoxide Hydrolases; C506428:EPHX2 protein, human
keywords: DNA-encoded chemical library; clinical trials; drug development; drug discovery; hydrolases