title: Cell-Based Selection Expands the Utility of DNA-Encoded Small-Molecule Library Technology to Cell Surface Drug Targets: Identification of Novel Antagonists of the NK3 Tachykinin Receptor.
abstract: DNA-encoded small-molecule library technology has recently emerged as a new paradigm for identifying ligands against drug targets. To date, this technology has been used with soluble protein targets that are produced and used in a purified state. Here, we describe a cell-based method for identifying small-molecule ligands from DNA-encoded libraries against integral membrane protein targets. We use this method to identify novel, potent, and specific inhibitors of NK3, a member of the tachykinin family of G-protein coupled receptors (GPCRs). The method is simple and broadly applicable to other GPCRs and integral membrane proteins. We have extended the application of DNA-encoded library technology to membrane-associated targets and demonstrate the feasibility of selecting DNA-tagged, small-molecule ligands from complex combinatorial libraries against targets in a heterogeneous milieu, such as the surface of a cell.
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline , Collegeville, Pennsylvania 19426, United States.
authors.forename: Zining
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline , Collegeville, Pennsylvania 19426, United States.
authors.forename: Todd L
authors.initials: TL
authors.lastname: Graybill
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline , Collegeville, Pennsylvania 19426, United States.
authors.forename: Xin
authors.initials: X
authors.lastname: Zeng
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline , Collegeville, Pennsylvania 19426, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Platchek
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline , Waltham, Massachusetts 02451, United States.
authors.forename: Jean
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline , Collegeville, Pennsylvania 19426, United States.
authors.forename: Vera Q
authors.initials: VQ
authors.lastname: Bodmer
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline , Collegeville, Pennsylvania 19426, United States.
authors.forename: David D
authors.initials: DD
authors.lastname: Wisnoski
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline , Collegeville, Pennsylvania 19426, United States.
authors.forename: Jianghe
authors.initials: J
authors.lastname: Deng
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline , Collegeville, Pennsylvania 19426, United States.
authors.forename: Frank T
authors.initials: FT
authors.lastname: Coppo
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline , Waltham, Massachusetts 02451, United States.
authors.forename: Gang
authors.initials: G
authors.lastname: Yao
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline , Waltham, Massachusetts 02451, United States.
authors.forename: Alex
authors.initials: A
authors.lastname: Tamburino
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline , Collegeville, Pennsylvania 19426, United States.
authors.forename: Genaro
authors.initials: G
authors.lastname: Scavello
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline , Waltham, Massachusetts 02451, United States.
authors.forename: G Joseph
authors.initials: GJ
authors.lastname: Franklin
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline , Waltham, Massachusetts 02451, United States.
authors.forename: Sibongile
authors.initials: S
authors.lastname: Mataruse
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline , Waltham, Massachusetts 02451, United States.
authors.forename: Katie L
authors.initials: KL
authors.lastname: Bedard
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline , Waltham, Massachusetts 02451, United States.
authors.forename: Yun
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline , Waltham, Massachusetts 02451, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Chai
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline , Waltham, Massachusetts 02451, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Summerfield
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline , Waltham, Massachusetts 02451, United States.
authors.forename: Paolo A
authors.initials: PA
authors.lastname: Centrella
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline , Waltham, Massachusetts 02451, United States.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Messer
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline , Collegeville, Pennsylvania 19426, United States.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Pope
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline , Waltham, Massachusetts 02451, United States.
authors.forename: David I
authors.initials: DI
authors.lastname: Israel
mesh_terms: D000085:Acetates / Q000737:chemistry / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D018042:Receptors, Neurokinin-3 / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000085:Acetates; D008024:Ligands; C444647:N-(alpha-ethylbenzyl)-3-(carboxymethoxy)-2-phenylquinoline-4-carboxamide; D011804:Quinolines; D018042:Receptors, Neurokinin-3; D054852:Small Molecule Libraries; D004247:DNA
keywords: DNA encoded chemical library; G-protein coupled receptor; affinity selection; cell-associated target protein; combinatorial chemistry; drug discovery