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  3. Allosteric "beta-blocker" isolated from a DNA-encoded small molecule library

Allosteric "beta-blocker" isolated from a DNA-encoded small molecule library

  • Proc Natl Acad Sci U S A. 2017 Feb 14;114(7):1708-1713. doi: 10.1073/pnas.1620645114.
Seungkirl Ahn 1,  Alem W Kahsai 1,  Biswaranjan Pani 1,  Qin-Ting Wang 2,  Shuai Zhao 2,  Alissa L Wall 1,  Ryan T Strachan 3,  Dean P Staus 1 4,  Laura M Wingler 1 4,  Lillian D Sun 1,  Justine Sinnaeve 1,  Minjung Choi 5,  Ted Cho 6,  Thomas T Xu 1,  Gwenn M Hansen 7,  Michael B Burnett 7,  Jane E Lamerdin 8,  Daniel L Bassoni 8,  Bryant J Gavino 8,  Gitte Husemoen 9,  Eva K Olsen 9,  Thomas Franch 9,  Stefano Costanzi 10,  Xin Chen 11,  Robert J Lefkowitz 12 4 5
Affiliations

Affiliations

  • 1 Department of Medicine, Duke University Medical Center, Durham, NC 27710.
  • 2 Department of Medicinal Chemistry, School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou 213164, Jiangsu, China.
  • 3 Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599.
  • 4 Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710.
  • 5 Department of Biochemistry, Duke University Medical Center, Durham, NC 27710.
  • 6 Department of Biology, Duke University Medical Center, Durham, NC 27710.
  • 7 Lexicon Pharmaceuticals, Inc., The Woodlands, TX 77381.
  • 8 DiscoverX Co., Fremont, CA 94538.
  • 9 Nuevolution A/S, 2100 Copenhagen, Denmark.
  • 10 Department of Chemistry, American University, Washington, DC 20016.
  • 11 Department of Medicinal Chemistry, School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou 213164, Jiangsu, China; lefko001@receptor-biol.duke.edu xinchen@cczu.edu.cn.
  • 12 Department of Medicine, Duke University Medical Center, Durham, NC 27710; lefko001@receptor-biol.duke.edu xinchen@cczu.edu.cn.
PMID: 28130548 DOI: 10.1073/pnas.1620645114
Abstract

The β2-adrenergic receptor (β2AR) has been a model system for understanding regulatory mechanisms of G-protein-coupled receptor (GPCR) actions and plays a significant role in cardiovascular and pulmonary diseases. Because all known β-adrenergic receptor drugs target the orthosteric binding site of the receptor, we set out to isolate allosteric ligands for this receptor by panning DNA-encoded small-molecule libraries comprising 190 million distinct compounds against purified human β2AR. Here, we report the discovery of a small-molecule negative allosteric modulator (antagonist), compound 15 [([4-((2S)-3-(((S)-3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)amino)-2-(2-cyclohexyl-2-phenylacetamido)-3-oxopropyl)benzamide], exhibiting a unique chemotype and low micromolar affinity for the β2AR. Binding of 15 to the receptor cooperatively enhances orthosteric inverse agonist binding while negatively modulating binding of orthosteric agonists. Studies with a specific antibody that binds to an intracellular region of the β2AR suggest that 15 binds in proximity to the G-protein binding site on the cytosolic surface of the β2AR. In cell-signaling studies, 15 inhibits cAMP production through the β2AR, but not that mediated by Other Gs-coupled receptors. Compound 15 also similarly inhibits β-arrestin recruitment to the activated β2AR. This study presents an allosteric small-molecule ligand for the β2AR and introduces a broadly applicable method for screening DNA-encoded small-molecule libraries against purified GPCR targets. Importantly, such an approach could facilitate the discovery of GPCR drugs with tailored allosteric effects.

Keywords

DNA-encoded small-molecule library; G-protein–coupled receptor; allosteric modulator; drug discovery; β2-adrenergic receptor.

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