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

被引：120

作者：

Ahn, Seungkirl ^{[1
]}

Kahsai, Alem W. ^{[1
]}

Pani, Biswaranjan ^{[1
]}

Wang, Qin-Ting ^{[2
]}

Zhao, Shuai ^{[2
]}

Wall, Alissa L. ^{[1
,11
]}

Strachan, Ryan T. ^{[3
]}

Staus, Dean P. ^{[1
,4
]}

Wingler, Laura M. ^{[1
,4
]}

Sun, Lillian D. ^{[1
,12
]}

Sinnaeve, Justine ^{[1
,13
]}

Choi, Minjung ^{[5
]}

Cho, Ted ^{[6
,14
]}

Xu, Thomas T. ^{[1
]}

Hansen, Gwenn M. ^{[7
,15
]}

Burnett, Michael B. ^{[7
,16
]}

Lamerdin, Jane E. ^{[8
]}

Bassoni, Daniel L. ^{[8
]}

Gavino, Bryant J. ^{[8
]}

Husemoen, Gitte ^{[9
]}

Olsen, Eva K. ^{[9
]}

Franch, Thomas ^{[9
]}

Costanzi, Stefano ^{[10
]}

Chen, Xin ^{[2
]}

Lefkowitz, Robert J. ^{[1
,4
,5
]}

机构：

[1] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA

[2] Changzhou Univ, Sch Pharmaceut Engn & Life Sci, Dept Med Chem, Changzhou 213164, Jiangsu, Peoples R China

[3] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA

[4] Duke Univ, Med Ctr, Howard Hughes Med Inst, Durham, NC 27710 USA

[5] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA

[6] Duke Univ, Med Ctr, Dept Biol, Durham, NC 27710 USA

[7] Lexicon Pharmaceut Inc, The Woodlands, TX 77381 USA

[8] DiscoverX Co, Fremont, CA 94538 USA

[9] Nuevolution AS, DK-2100 Copenhagen, Denmark

[10] Amer Univ, Dept Chem, Washington, DC 20016 USA

[11] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA

[12] Case Western Reserve Univ, Cleveland Clin, Lerner Coll Med, Cleveland, OH 44195 USA

[13] Vanderbilt Univ, Sch Med, Dept Cell & Dev Biol, Nashville, TN 37240 USA

[14] Georgetown Univ, Sch Med, Washington, DC 20007 USA

[15] Nurix Inc, Lib Discovery Team, San Francisco, CA 94158 USA

[16] Bethyl Labs Inc, Montgomery, TX 77356 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2017年 / 114卷 / 07期

基金：

美国国家科学基金会; 美国国家卫生研究院;

关键词：

G-protein-coupled receptor; beta(2)-adrenergic receptor; allosteric modulator; DNA-encoded small molecule library; drug discovery; PROTEIN-COUPLED RECEPTORS; ARRESTIN RECRUITMENT; LIGAND BIAS; SELECTION; MECHANISM; BINDING; SPACE;

D O I：

10.1073/pnas.1620645114

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The beta(2)-adrenergic receptor (beta(2)AR) 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 beta-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 beta(2)AR. 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-(2cyclohexyl-2-phenylacetamido)-3-oxopropyl) benzamide], exhibiting a unique chemotype and low micromolar affinity for the beta(2)AR. 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 beta(2)AR suggest that 15 binds in proximity to the G-protein binding site on the cytosolic surface of the beta(2)AR. In cell-signaling studies, 15 inhibits cAMP production through the beta(2)AR, but not that mediated by other Gs-coupled receptors. Compound 15 also similarly inhibits beta-arrestin recruitment to the activated beta(2)AR. This study presents an allosteric small-molecule ligand for the beta(2)AR 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.

引用

页码：1708 / 1713

页数：6

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