Expanding the horizons of targeted protein degradation: A non-small molecule perspective

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(6), P. 2402 - 2427

Published: Jan. 21, 2024

Targeted protein degradation (TPD) represented by proteolysis targeting chimeras (PROTACs) marks a significant stride in drug discovery. A plethora of innovative technologies inspired PROTAC have not only revolutionized the landscape TPD but potential to unlock functionalities beyond degradation. Non-small-molecule-based approaches play an irreplaceable role this field. wide variety agents spanning broad chemical spectrum, including peptides, nucleic acids, antibodies, and even vaccines, which prove instrumental overcoming constraints conventional small molecule entities also provided rapidly renewing paradigms. Herein we summarize burgeoning non-small technological platforms PROTACs, three major trajectories, provide insights for design strategies based on novel

Language: Английский

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Innovative, combinatorial and high-throughput approaches to degrader synthesis

Chemical Society Reviews, Journal Year: 2024, Volume and Issue: 53(10), P. 4838 - 4861

Published: Jan. 1, 2024

In this review we highlight how the synthesis of degraders has evolved in recent years, particular application high-throughput chemistry and screening approaches such as D2B DEL technologies to expedite discovery timelines.

Language: Английский

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Molecular Glue-Mediated Targeted Protein Degradation: A Novel Strategy in Small-Molecule Drug Development

iScience, Journal Year: 2024, Volume and Issue: 27(9), P. 110712 - 110712

Published: Aug. 23, 2024

Small-molecule drugs are effective and thus most widely used. However, their applications limited by reliance on active high-affinity binding sites, restricting target options. A breakthrough approach involves molecular glues, a novel class of small-molecule compounds capable inducing protein-protein interactions (PPIs). This opens avenues to conventionally undruggable proteins, overcoming limitations seen in conventional drugs. Molecular glues play key role targeted protein degradation (TPD) techniques, including ubiquitin-proteasome system-based approaches such as proteolysis targeting chimeras (PROTACs) glue degraders recently emergent lysosome techniques like extracellular proteins through the asialoglycoprotein receptors (MoDE-As) macroautophagy (MADTACs). These enable an innovative strategy for prolonged inhibition pathology-associated proteins. review provides overview them, emphasizing clinical potential guiding development molecular-glue-mediated TPD techniques.

Language: Английский

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Discovery of Molecular Glue Degraders via Isogenic Morphological Profiling

ACS Chemical Biology, Journal Year: 2023, Volume and Issue: 18(12), P. 2464 - 2473

Published: Nov. 21, 2023

Molecular glue degraders (MGDs) are small molecules that degrade proteins of interest via the ubiquitin–proteasome system. While MGDs were historically discovered serendipitously, approaches for MGD discovery now include cell-viability-based drug screens or data mining public transcriptomics and response datasets. These approaches, however, have target spaces restricted to essential proteins. Here we develop a high-throughput workflow also reaches nonessential proteome. This begins with rapid synthesis compound library by sulfur(VI) fluoride exchange chemistry coupled morphological profiling assay in isogenic cell lines vary levels E3 ligase CRBN. By comparing changes induced treatment across lines, able identify FL2-14 as CRBN-dependent targeting protein GSPT2. We envision this would contribute characterization wider range

Language: Английский

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Characterizing the Cooperative Effect of PROTAC Systems with End-Point Binding Free Energy Calculation

Journal of Chemical Information and Modeling, Journal Year: 2024, Volume and Issue: 64(19), P. 7666 - 7678

Published: Oct. 3, 2024

Proteolytic targeting chimeras (PROTACs), as an emerging type of drug, function by proximity-based modalities that narrow the distance between a target protein and E3 ubiquitin ligase to facilitate ubiquitination labeling for degradation. Although it is evidenced cooperativity PROTAC ternary interaction one key factors affecting degradation rate protein, design utilizing this indicator still challenging because complicated/flexible interactions in target-PROTAC-E3 system. Therefore, developing reliable practicable computational methods great interest design. Hence, study, we investigate feasibility using end-point binding free energy calculation method, represented molecular mechanics/Poisson-Boltzmann (generalized-Born) surface area (MM/PB(GB)SA), characterizing (including stabilization hook effects) systems. The result shows MM/GBSA good predictor these effects under relatively long dynamics adjustment (50-100 ns) low dielectric constant (ε

Language: Английский

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Application of DELs for E3 Ligase Ligand Discovery and Targeted Protein Degradation

Royal Society of Chemistry eBooks, Journal Year: 2025, Volume and Issue: unknown, P. 134 - 156

Published: Feb. 21, 2025

Targeted protein degradation (TPD) provides new therapeutic opportunities beyond traditional inhibitors. TPD relies on the ability to induce proximity between an E3 ligase and target of interest, harnessing ubiquitin proteasome system ubiquitylate degrade target. This can be induced by either monofunctional ligands (molecular glues) or bifunctional molecules that tether ligases together. DNA encoded libraries (DELs) provide rapid access diverse chemical space for ligand discovery and, their design, facilitate development both molecular glues degraders.

Language: Английский

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A Multicomponent Reaction-Based Platform Opens New Avenues in Aryl Hydrocarbon Receptor Modulation

ACS Central Science, Journal Year: 2025, Volume and Issue: unknown

Published: April 10, 2025

A multidisciplinary platform is presented to address aryl hydrocarbon receptor (AhR) modulation. rewired Yonemitsu multicomponent reaction with indole 2-carboxaldehydes and nucleophilic species was designed access a family of 6-substituted indolocarbazoles. The conformational behavior these compounds examined rationalize their axial chirality. In silico docking molecular simulations highlighted key features implicated in binding AhR. Furthermore, the synthesis linkable derivatives allowed direct development conjugated entities. Reporter gene target expression analyses identified novel structures as potent noncytotoxic activating AhR ligands, that can be extended bifunctional molecules. anti-inflammatory properties agonists were assessed interleukin-13 treated keratinocytes. Altogether, synergistic research synthetic computational chemistry integrated biological studies opens avenues toward understanding roles targeted therapeutics.

Language: Английский

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Selection of DNA-encoded Chemical Libraries for Compounds that can Induce Protein Ubiquitination

Published: Feb. 12, 2024

We report a selection method of DNA-encoded libraries (DELs) that can identify the compounds able to induce ubiquitination protein intertest (POI). Since readout is based on POI ubiquitination, rather than binding or ternary complex formation, identified are more functionally relevant and predicative active degraders. In this study, by selecting DEL 950 different combinations ligands, linkers, E3 ligase ligands against BD1 domain bromodomain-containing 4 (BRD4-BD1) in presence absence ATP, we have potent BRD4-BD1 degrader (DC50: ~9.7 nM) also short-isoform-selective BRD4 0.26 μM). Furthermore, show formation may induced stable complexes but inactive This approach be an efficient broadly applicable for discovering functional degraders, as well harnessing vast chemical diversity DELs.

Language: Английский

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Extrapolating Lessons from Targeted Protein Degradation to Other Proximity-Inducing Drugs

ACS Chemical Biology, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 12, 2024

Targeted protein degradation (TPD) is an emerging pharmacologic strategy. It relies on small-molecule "degraders" that induce proximity of a component E3 ubiquitin ligase complex and target to ubiquitination subsequent proteasomal degradation. Essentially, degraders thus expand the function ligases, allowing them degrade proteins they would not recognize in absence small molecule. Over past decade, insights gained from identifying, designing, characterizing various have significantly enhanced our understanding TPD mechanisms, precipitating rational degrader discovery strategies. In this Account, I aim explore how these can be extrapolated anticipate both opportunities challenges utilizing overarching concept proximity-inducing pharmacology manipulate other cellular circuits for dissection biological mechanisms therapeutic purposes.

Language: Английский

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The 17^th EFMC Short Course on Medicinal Chemistry on Small Molecule Protein Degraders

ChemMedChem, Journal Year: 2023, Volume and Issue: 18(20)

Published: Oct. 10, 2023

The 17th EFMC Short Course on Medicinal Chemistry took place April 23-26, 2023 in Oegstgeest, near Leiden the Netherlands. It covered for first time exciting topic of Targeted Protein Degradation (full title: Small Molecule Degraders: A New Opportunity Drug Design and Development). course was oversubscribed, with 35 attendees 6 instructors mainly from Europe but also US South Africa, representing both industry academia. This report summarizes successful event, key lectures given topics discussed.

Language: Английский

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