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  • An Erratum to this article was published on 01 October 2009

This article has been updated

Abstract

Biochemical combinatorial techniques such as phage display, RNA display and oligonucleotide aptamers have proven to be reliable methods for generation of ligands to protein targets. Adapting these techniques to small synthetic molecules has been a long-sought goal. We report the synthesis and interrogation of an 800-million-member DNA-encoded library in which small molecules are covalently attached to an encoding oligonucleotide. The library was assembled by a combination of chemical and enzymatic synthesis, and interrogated by affinity selection. We describe methods for the selection and deconvolution of the chemical display library, and the discovery of inhibitors for two enzymes: Aurora A kinase and p38 MAP kinase.

  • Compound

    2-(4-(2-(4-(Cyclopropanecarboxamido)phenylthio)-6-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-4-yl)piperazin-1-yl)acetic acid

  • Compound

    3-(4-((3-(Aminomethyl)cyclohexyl)methylamino)-6-(3,3-dimethylbutan-2-ylamino)-1,3,5-triazin-2-ylamino)-N-methoxy-4-methylbenzamide

  • Compound

    3-(4-((3-(Aminomethyl)cyclohexyl)methylamino)-6-(cyclohexylamino)-1,3,5-triazin-2-ylamino)-N-methoxy-4-methylbenzamide

  • Compound

    3-(4-(3,3-Dimethylbutan-2-ylamino)-6-(3-methylbenzylamino)-1,3,5-triazin-2-ylamino)-N-methoxy-4-methylbenzamide

  • Compound

    N-Methoxy-4-methyl-3-(4-(methyl(neopentyl)amino)-6-(piperazin-1-yl)-1,3,5-triazin-2-ylamino)benzamide

  • Compound

    2-(4-(Butyl(methyl)amino)-6-(2-methoxyphenethylamino)-1,3,5-triazin-2-ylamino)-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)propanamide

  • Compound

    N2-(2-(1H-Pyrrolo[2,3-b]pyridin-3-yl)ethyl)-N4-butyl-N6-(2-methoxyphenethyl)-N4-methyl-1,3,5-triazine-2,4,6-triamine

  • Compound

    2-(4-(2-Methoxyphenethylamino)-6-(methyl((S)-1-phenylethyl)amino)-1,3,5-triazin-2-ylamino)-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)propanamide

  • Compound

    2-(4-(2-Methoxyphenethylamino)-6-(quinolin-6-ylamino)-1,3,5-triazin-2-ylamino)-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)propanamide

  • Compound

    N2-(3,4-Dimethoxyphenyl)-N4-(2-fluorophenethyl)-N6-(quinolin-6-yl)-1,3,5-triazine-2,4,6-triamine

  • Compound

    2-(4-(3,4-Dimethoxyphenylamino)-6-(quinolin-6-ylamino)-1,3,5-triazin-2-ylamino)-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)propanamide

  • Compound

    N2-(2-Methoxyphenethyl)-N4-methyl-N6-(quinolin-6-yl)-1,3,5-triazine-2,4,6-triamine

  • Compound

    (S)-3-(2,2-Dimethyl-4H-benzo[d][1,3]dioxin-6-yl)-2-(4-(isobutylamino)-6-(5-(1,2,3,4-tetrahydroquinoline-1-carbonyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazin-2-ylamino)-N-methylpropanamide

  • Compound

    (S)-3-(2,2-Dimethyl-4H-benzo[d][1,3]dioxin-6-yl)-2-(4-(isobutylamino)-6-(6-(1,2,3,4-tetrahydroquinoline-1-carbonyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazin-2-ylamino)-N-methylpropanamide

  • Compound

    (S)-3-(2,2-Dimethyl-4H-benzo[d][1,3]dioxin-6-yl)-2-(4-ethoxy-6-(5-(1,2,3,4-tetrahydroquinoline-1-carbonyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazin-2-ylamino)-N-methylpropanamide

  • Compound

    (S)-3-(2,2-Dimethyl-4H-benzo[d][1,3]dioxin-6-yl)-2-(4-ethoxy-6-(6-(1,2,3,4-tetrahydroquinoline-1-carbonyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazin-2-ylamino)-N-methylpropanamide

  • Compound

    (S)-3-(2,2-Dimethyl-4H-benzo[d][1,3]dioxin-6-yl)-2-(4-hydroxy-6-(5-(1,2,3,4-tetrahydroquinoline-1-carbonyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazin-2-ylamino)-N-methylpropanamide

  • Compound

    (S)-3-(2,2-Dimethyl-4H-benzo[d][1,3]dioxin-6-yl)-2-(4-hydroxy-6-(6-(1,2,3,4-tetrahydroquinoline-1-carbonyl)-1H-benzo[d]imidazol-1-yl)-1,3,5-triazin-2-ylamino)-N-methylpropanamide

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Change history

  • 17 September 2009

    In the version of this article initially published, the IC50 values in the table in Figure 3c were listed as nM instead of μM. The error has been corrected in the HTML and PDF versions of the article.

Accessions

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Author information

Author notes

    • Matthew A Clark
    • , Raksha A Acharya
    • , Christopher C Arico-Muendel
    • , Svetlana L Belyanskaya
    • , Dennis R Benjamin
    • , Neil R Carlson
    • , Paolo A Centrella
    • , Cynthia H Chiu
    • , Steffen P Creaser
    • , John W Cuozzo
    • , Christopher P Davie
    • , Yun Ding
    • , G Joseph Franklin
    • , Kurt D Franzen
    • , Malcolm L Gefter
    • , Steven P Hale
    • , Nils J V Hansen
    • , David I Israel
    • , Jinwei Jiang
    • , Malcolm J Kavarana
    • , Michael S Kelley
    • , Christopher S Kollmann
    • , Fan Li
    • , Kenneth Lind
    • , Sibongile Mataruse
    • , Patricia F Medeiros
    • , Jeffrey A Messer
    • , Paul Myers
    • , Heather O'Keefe
    • , Matthew C Oliff
    • , Cecil E Rise
    • , Alexander L Satz
    • , Steven R Skinner
    • , Jennifer L Svendsen
    • , Lujia Tang
    • , Kurt van Vloten
    • , Richard W Wagner
    • , Gang Yao
    •  & Barry A Morgan

    Present addresses: GlaxoSmithKline, Molecular Discovery Research Boston, Waltham, Massachusetts, USA (M.A.C., C.C.A.-M., S.L.B., N.R.C., P.A.C., C.H.C., J.W.C., C.P.D., Y.D., G.J.F., D.I.I., M.S.K., C.S.K., K.L., P.F.M., J.A.M., H.O., C.E.R., A.L.S., S.R.S., G.Y. and B.A.M.); Bedford, Massachusetts, USA (R.A.A.); Seattle Genetics, Inc., Bothell, Washington, USA (D.R.B.); Satori Pharmaceuticals, Cambridge, Massachusetts, USA (S.P.C.); ParagonDx, LLC, Morrisville, North Carolina, USA (K.D.F.); Lincoln, Massachusetts, USA (M.L.G.); Ensemble Discovery Corporation, Cambridge, Massachusetts, USA (S.P.H.); Vipergen, Copenhagen, Denmark (N.J.V.H.); AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts, USA (J.J.); Foley & Lardner LLP, Washington, DC, USA (M.J.K.); Medway, Massachusetts, USA (F.L.); Massachusetts College of Pharmacy and Health Sciences, Worcester, Massachusetts, USA (S.M. and J.L.S.); Monsanto, Cambridge, Massachusetts, USA (P.M.); Columbia University, College of Physicians and Surgeons, New York, New York, USA (M.C.O.); Novartis Pharmaceuticals, Cambridge, Massachusetts, USA (L.T.); Biogen IDEC, Cambridge, Massachusetts, USA (K.v.V.); SRU Biosystems, Woburn, Massachusetts, USA (R.W.W.).

Affiliations

  1. The former Praecis Pharmaceuticals, Waltham, Massachusetts, USA, presently GlaxoSmithKline, Molecular Discovery Research Boston, Waltham, Massachusetts, USA.

    • Matthew A Clark
    • , Raksha A Acharya
    • , Christopher C Arico-Muendel
    • , Svetlana L Belyanskaya
    • , Dennis R Benjamin
    • , Neil R Carlson
    • , Paolo A Centrella
    • , Cynthia H Chiu
    • , Steffen P Creaser
    • , John W Cuozzo
    • , Christopher P Davie
    • , Yun Ding
    • , G Joseph Franklin
    • , Kurt D Franzen
    • , Malcolm L Gefter
    • , Steven P Hale
    • , Nils J V Hansen
    • , David I Israel
    • , Jinwei Jiang
    • , Malcolm J Kavarana
    • , Michael S Kelley
    • , Christopher S Kollmann
    • , Fan Li
    • , Kenneth Lind
    • , Sibongile Mataruse
    • , Patricia F Medeiros
    • , Jeffrey A Messer
    • , Paul Myers
    • , Heather O'Keefe
    • , Matthew C Oliff
    • , Cecil E Rise
    • , Alexander L Satz
    • , Steven R Skinner
    • , Jennifer L Svendsen
    • , Lujia Tang
    • , Kurt van Vloten
    • , Richard W Wagner
    • , Gang Yao
    •  & Barry A Morgan
  2. GlaxoSmithKline, Computational and Structural Chemistry, King of Prussia, Pennsylvania, USA.

    • Baoguang Zhao

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Corresponding author

Correspondence to Barry A Morgan.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Methods

Excel files

  1. 1.

    Supplementary Dataset 1

    DEL-A Synthon List

  2. 2.

    Supplementary Dataset 2

    DEL-B Synthon List

  3. 3.

    Supplementary Dataset 3

    DEL-A Selection - p38 MAPK

  4. 4.

    Supplementary Dataset 4

    DEL-A Selection - Aurora A, Method A

  5. 5.

    Supplementary Dataset 5

    DEL-A Selection - Aurora A, Method B

  6. 6.

    Supplementary Dataset 6

    DEL-B Selection - p38 MAPK

About this article

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DOI

https://doi.org/10.1038/nchembio.211

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