RSC Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 16(3), P. 1141 - 1150
Published: Dec. 23, 2024
High-throughput chemistry (HTC) and direct-to-biology (D2B) platforms allow for plate-based compound synthesis biological evaluation of crude mixtures in cellular assays.
Language: Английский
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
Citations
9
Cells, Journal Year: 2024, Volume and Issue: 13(7), P. 578 - 578
Published: March 26, 2024
Proteolysis-targeting chimeras (PROTACs) describe compounds that bind to and induce degradation of a target by simultaneously binding ubiquitin ligase. More generally referred as bifunctional degraders, PROTACs have led the way in field targeted protein (TPD), with several currently undergoing clinical testing. Alongside single-moiety compounds, or molecular glue degraders (MGDs), are increasingly being considered viable approach for development therapeutics, driven advances rational discovery approaches. This review focuses on drug respect within proteasome system, including analysis mechanistic concepts approaches, an overview current pre-clinical degrader status oncology, neurodegenerative inflammatory disease.
Language: Английский
Citations
7
Cell Reports Physical Science, Journal Year: 2024, Volume and Issue: 5(8), P. 102139 - 102139
Published: Aug. 1, 2024
Highlights•A light-induced one-pot coupling of PROTAC-like molecules•Cyclic ethers used as linker precursors without any pre-assembly procedure•Reactions complete within 4 h up to 95% yield with a high regioselectivity•A wide substrate scope gave triazole-based linkers structural diversitySummaryProteolysis-targeting chimeras (PROTACs) are powerful approach for targeted protein degradation. One the current bottlenecks developing PROTACs is lack an operationally simple linkerology rapidly construct various linkers. The classic convergent synthesis strategy by pre-assembled two ligands stepwise commonly needs at least four steps give final target PROTACs, which results in low total yields long reaction times (several days) and tedious operations. Here, we develop efficient photocatalytic rapid analogs containing linker-pre-assembled procedure. was completed room temperature. Easily accessible cyclic directly furnish fashion, including alkenyl, polyethylene glycol (PEG), ketone, cyclohexane chains. study provides highly efficient, step-economic, simple, environmentally friendly PROTAC drug discovery.Graphical abstract
Language: Английский
Citations
5
The Journal of Organic Chemistry, Journal Year: 2025, Volume and Issue: unknown
Published: Feb. 2, 2025
Ultra high-throughput chemistry carried out in 1536-well plates is increasingly utilized for reaction optimization protocols and direct-to-biology (D2B) platforms, where nanomolar quantities of the final product are directly assessed biochemical or cellular activity without purification. As their popularity increases, it crucial that synthesis these molecules reliable reproducible. Research our laboratories has identified several nuances amide couplings when performed on nanoscale result poor translation from to batch-scale reactions. This case study presents a coupling synthesize 700 PROTAC molecules, which range factors success nanoscale, despite having no influence conversion batch. work guide chemists consider working importance drawing conclusions synthesis.
Language: Английский
Citations
0
ACS Chemical Biology, Journal Year: 2025, Volume and Issue: unknown
Published: Feb. 11, 2025
Proteolysis targeting chimeras (PROTACs) have gained considerable attention as a new modality in drug discovery. The development of PROTACs has been mainly focused on using CRBN (Cereblon) and VHL (Von Hippel-Lindau ligase) E3 ligase ligands. However, the size human family, newly developed ligands, favorable druggability some families hold promise that novel degraders with unique pharmacological properties will be designed future this large space. Here, we workflow aiming to improve streamline evaluation ligand efficiency for PROTAC assessment corresponding "degradable" target space broad-spectrum kinase inhibitors well-established VH032 validation system. Our study revealed linker attachment points are highly efficient degradation well pitfalls when protein readout. For instance, cytotoxicity was identified major mechanism leading PROTAC- VHL-independent degradation. combination negative controls, competition by parent compounds, neddylation proteasome essential distinguish between VHL-dependent -independent events. We share here findings limitations our hope provide guidance evaluations systems degrader development.
Language: Английский
Citations
0
European Journal of Organic Chemistry, Journal Year: 2025, Volume and Issue: unknown
Published: Feb. 18, 2025
Abstract Amide bonds are ubiquitous in molecules of interest such as pharmaceuticals, natural products, and agrochemicals. Over the last decades, significant efforts have been directed at developing efficient methods for formation this class chemical bonds. Herein, we disclose a robust, user‐friendly approach rapid parallel synthesis amide‐containing compounds, good yield purity. Our utilizes automated technologies pre‐packed capsules containing all necessary materials reaction work‐up. Following manual addition amine carboxylic acid, product isolation is achieved automatically standardized, integrated manner. This methodology tolerates wide diversity acids amines (or salts). To accelerate discovery rapidly create compound libraries, method was miniaturized into an format, using 96‐well plate kits, which could be beneficial to medicinal chemists.
Language: Английский
Citations
0
European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 289, P. 117432 - 117432
Published: Feb. 20, 2025
Language: Английский
Citations
0
Published: April 18, 2025
Abstract High-throughput screening (HTS) of (large) compound collections is a critical early step in many drug discovery programs, enabling the rapid identification lead molecules with desirable biological activity. The success HTS depends heavily on quality libraries used, and as such, development targeted has emerged promising approach to enhance effectiveness efforts. However, acquisition synthesis such remain costly labor-intensive, often yielding quantities far exceeding small amounts required for screening. To address these challenges, we present high-throughput synthesis-to-screening method efficient inplate generation immediate deubiquitinase (DUB)-focused library. Central our use an Echo acoustic liquid handler, which enables precise nanoliter-scale transfers DMSO-based solutions, facilitating miniaturized directly 1,536-well plates. Using this platform, constructed library 7,536 compounds featuring DUB-privileged cyanimide warhead screened it against panel twelve DUBs ubiquitin-like proteases. This identified two structurally related selective inhibitory activity interferon-stimulated gene 15 (ISG15) protease USP18, further developed into first-in-class USP18 inhibitor 35 nM potency. compound, BB07CA902, demonstrated exceptional specificity across 41 effectively increased ISGylation levels cells by inhibiting With technology, enabled preparation large DUB-targeted cyanimide-based libraries, will accelerate future DUB development.
Language: Английский
Citations
0
Drug Discovery Today, Journal Year: 2024, Volume and Issue: 29(10), P. 104143 - 104143
Published: Aug. 23, 2024
Language: Английский
Citations
2
RSC Medicinal Chemistry, Journal Year: 2024, Volume and Issue: unknown
Published: Nov. 7, 2024
PROTACs are an emerging therapeutic approach towards targeted protein degradation. This article examines the leading examples of this modality that in clinical development through prism their physicochemical properties.
Language: Английский
Citations
2