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

Ahn, Seungkirl; Kahsai, Alem W.; Pani, Biswaranjan; Wang, Qinting; Zhao, Shuai; Wall, Alissa L.; Strachan, Ryan T.; Staus, Dean P.; Wingler, Laura M.; Sun, Lillian; Sinnaeve, Justine; Choi, Min-Jung; Cho, Ted; Xu, Thomas T.; Hansen, Gwenn M.; Burnett, Michael B.; Lamerdin, Jane E.; Bassoni, Daniel L.; Gavino, Bryant J.; Husemoen, Gitte; Olsen, Eva K.; Franch, Thomas; Costanzi, Stefano; Chen, Xin; Lefkowitz, Robert J.

doi:10.1073/pnas.1620645114

Cited by 126 publications

(124 citation statements)

References 43 publications

(53 reference statements)

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“…As suggested from previous studies 1 , Cmpd-15PA binds to the intracellular surface of the β 2 AR. It lies partially buried in a pocket formed by TMs 1, 2, 6, 7, helix 8 (H8) and intracellular loop 1 (ICL1) (Fig.…”

supporting

confidence: 60%

“…The majority of GPCR crystal structures published to date were obtained with receptors bound to orthosteric antagonists, and only a few structures bound to allosteric ligands have been reported. Compound 15 (Cmpd-15) is an allosteric modulator of the β 2 adrenergic receptor (β 2 AR) that was recently isolated from a DNA-encoded small-molecule library 1 . Orthosteric β-adrenergic receptor antagonists, known as beta-blockers, are amongst the most prescribed drugs in the world and Cmpd-15 is the first allosteric beta-blocker.…”

mentioning

confidence: 99%

“…Previously, several groups have reported modulators binding within the intracellular surface of GPCRs 3,4 and to the outer surface of transmembrane segments 5 . Cmpd-15, 4-((2 S )-3-((( S )-3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)amino)-2-(2-cyclohexyl-2-phenylacetamido)-3-oxopropyl)benzamide, is a membrane-permeable negative allosteric modulator of β 2 AR that was isolated from a DNA-encoded small-molecule library 1 . Of interest, unlike conventional drug discovery methods, this screen using purified β 2 AR protein unoccupied by any ligand was unbiased, allowing us to identify molecules capable of binding to any surface of the receptor, not just the orthosteric pocket.…”

mentioning

confidence: 99%

“…1b) and positive cooperativity for the inverse agonist ICI-118,551 (ref. 1). We previously reported the structure of the β 2 AR bound to an allosteric nanobody (Nb60) that stabilized the inactive state 9 .…”

mentioning

confidence: 99%

“…Cmpd-15 is more efficacious at inhibiting β 2 AR activities than β 1 AR 1 , although all of the 21 amino acids that form the Cmpd-15 binding pocket are conserved except for Phe61 at the cytoplasmic end of TM1 and Lys267 6.29 in TM6, which are Thr and Arg in the homologous position of the β 1 AR (Extended Data Fig. 8a, b).…”

mentioning

confidence: 99%

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Mechanism of intracellular allosteric β2AR antagonist revealed by X-ray crystal structure

Liu

Ahn

Kahsai

et al. 2017

Nature

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159

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G-protein-coupled receptors (GPCRs) pose challenges for drug discovery efforts because of the high degree of structural homology in the orthosteric pocket, particularly for GPCRs within a single subfamily, such as the nine adrenergic receptors. Allosteric ligands may bind to less-conserved regions of these receptors and therefore are more likely to be selective. Unlike orthosteric ligands, which tonically activate or inhibit signalling, allosteric ligands modulate physiologic responses to hormones and neurotransmitters, and may therefore have fewer adverse effects. The majority of GPCR crystal structures published to date were obtained with receptors bound to orthosteric antagonists, and only a few structures bound to allosteric ligands have been reported. Compound 15 (Cmpd-15) is an allosteric modulator of the β2 adrenergic receptor (β2AR) that was recently isolated from a DNA-encoded small-molecule library1. Orthosteric β-adrenergic receptor antagonists, known as beta-blockers, are amongst the most prescribed drugs in the world and Cmpd-15 is the first allosteric beta-blocker. Cmpd-15 exhibits negative cooperativity with agonists and positive cooperativity with inverse agonists. Here we present the structure of the β2AR bound to a polyethylene glycol-carboxylic acid derivative (Cmpd-15PA) of this modulator. Cmpd-15PA binds to a pocket formed primarily by the cytoplasmic ends of transmembrane segments 1, 2, 6 and 7 as well as intracellular loop 1 and helix 8. A comparison of this structure with inactive- and active-state structures of the β2AR reveals the mechanism by which Cmpd-15 modulates agonist binding affinity and signalling.

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confidence: 60%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Mechanism of intracellular allosteric β2AR antagonist revealed by X-ray crystal structure

Liu

Ahn

Kahsai

et al. 2017

Nature

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159

163

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Screening and Characterizing of GPCR –Ligand Interactions with Mass Spectrometry‐Based Technologies

Qin

Wang

2022

GPCRs as Therapeutic Targets

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DNA‐Encoded Libraries: Aryl Fluorosulfonates as Versatile Electrophiles Enabling Facile On‐DNA Suzuki, Sonogashira, and Buchwald Reactions

Wang

et al. 2019

Advanced Science

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are encoded by unique DNA sequences as identification "barcodes," and are assembled combinatorial using split-andpool strategy or alternative procedures via DNA-compatible reactions. [7][8][9] DELs comprising millions or even billions of DNA-tagged druglike molecules can be effectively synthesized via this technology and screened against various protein targets of interest in a single pooled assay. In a typical affinity-based selection experiment, when non-and low-affinity binders are washed away, the DNA tag of the remaining compounds can be amplified using polymerase chain reaction and the relative frequency of the remaining compounds before and after selection is determined by counting the number of DNA tags in high-throughput DNA sequencing experiments. [10,11] To date, a large number of high-quality hits have been identified by the DEL technology for various therapeutically relevant targets, such as kinases, [12] phosphatases, [13] and G-protein coupled receptors. [14] Several drug candidates derived from their corresponding DEL hits, such as soluble epoxide hydrolase inhibitor GSK2256294, and death domain receptor-associated adaptor kinase RIP1 inhibitor GSK2982772 have progressed to latestage clinical development, [15,16] further emphasizing DEL as a powerful technology for small molecular drug discovery.Despite these successes, the great potential of DEL technology in drug discovery has not yet been fully realized. One of the most fundamental challenges is the synthesis of high-quality libraries with more structural diversity, which in turn depends on the development of new and robust DNA-compatible reactions that allow more flexibility in DEL's design and synthesis. Among various DNA-compatible reactions developed in recent years, transition-metal-promoted reactions such as Suzuki-Miyaura coupling, [17][18][19][20][21][22][23] Sonogashira coupling, and Buchwald-Hartwig amination using DNA-conjugated aryl halides as electrophiles have been elegantly developed (Figure 1), [24][25][26] and some of them have been developed for DEL synthesis. However, the environmental toxicity and high costs of aryl halides have hindered their large-scale applications in industry. Thus, much attention has been paid to phenol-derived electrophiles recently, [27] which, as compared to aryl halides, offer a more sustainable starting material because most of them are readily available from biomass. [28] In addition, phenol modules are also important components of natural products (NPs), bioactive molecules, and pharmaceutical drugs. Coupling reactions with Using (hetero)aryl fluorosulfonates as versatile electrophiles, facile on-DNA cross-coupling reactions of Suzuki, Sonogashira, and Buchwald are reported here. Notably, all of these reactions show excellent functional group tolerance, mild reaction conditions (relative low temperature and open to air), rich heterocyclic coupling partners, and more importantly, DNA-compatibility. Thus, these new reactions based on efficient formation of C(sp 2 )-C(sp 2 ), C(sp 2 )-C(sp), and C(s...

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

Cited by 126 publications

References 43 publications

Mechanism of intracellular allosteric β2AR antagonist revealed by X-ray crystal structure

Mechanism of intracellular allosteric β2AR antagonist revealed by X-ray crystal structure

Screening and Characterizing of GPCR –Ligand Interactions with Mass Spectrometry‐Based Technologies

DNA‐Encoded Libraries: Aryl Fluorosulfonates as Versatile Electrophiles Enabling Facile On‐DNA Suzuki, Sonogashira, and Buchwald Reactions

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