Publisher Correction: Rational discovery of molecular glue degraders via scalable chemical profiling

Mayor‐Ruiz, Cristina; Bauer, Sophie; Brand, Matthias; Kozicka, Zuzanna; Siklos, Marton I.; Imrichová, Hana; Kaltheuner, Ines H.; Hahn, Elisa; Seiler, Kristina; Koren, Anna; Petzold, Georg; Fellner, Michaela; Bock, Christoph; Müller, André C.; Zuber, Johannes; Geyer, Matthias; Thomä, Nicolas H.; Kubicek, Stefan; Ciulli, Alessio

doi:10.1038/s41589-021-00735-4

Cited by 6 publications

(9 citation statements)

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“…Paclitaxel (PTX) is a cancer chemotherapeutic agent of the taxane family; [ 22 ] however, the clinical usage of PTX is limited due to intrinsic and acquired resistance. [ 23 ] Thus, a significant effort is currently being directed toward improving its efficacy by combining it with different agents. [ 24 ] We demonstrated here that co‐treatment of C1 and PTC exhibited a synergistic anti‐cancer effect against TNBC, providing a novel combination treatment to sensitize the efficacy of PTX against TNBC.…”

Section: Discussionmentioning

confidence: 99%

“…[11] The serendipitous discovery of molecular glues offered researchers solutions to unmarketable target proteins. In recent years, an increasing number of inhibitors have been found to degrade target proteins via molecular glues mechanisms and play a role in cancer treatment including CDK inhibitors, [21] which offer an alternative approach to innovative drug discovery through targeted protein degradation.…”

Section: Discussionmentioning

confidence: 99%

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Design and Characterization of a Novel eEF2K Degrader with Potent Therapeutic Efficacy Against Triple‐Negative Breast Cancer

Zhong,

Zhu,

Jiang

et al. 2023

Advanced Science

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Dysregulated eEF2K expression is implicated in the pathogenesis of many human cancers, including triple‐negative breast cancer (TNBC), making it a plausible therapeutic target. However, specific eEF2K inhibitors with potent anti‐cancer activity have not been available so far. Targeted protein degradation has emerged as a new strategy for drug discovery. In this study, a novel small molecule chemical is designed and synthesized, named as compound C1, which shows potent activity in degrading eEF2K. C1 selectively binds to F8, L10, R144, C146, E229, and Y236 of the eEF2K protein and promotes its proteasomal degradation by increasing the interaction between eEF2K and the ubiquitin E3 ligase βTRCP in the form of molecular glue. C1 significantly inhibits the proliferation and metastasis of TNBC cells both in vitro and in vivo and in TNBC patient‐derived organoids, and these antitumor effects are attributed to the degradation of eEF2K by C1. Additionally, combination treatment of C1 with paclitaxel, a commonly used chemotherapeutic drug, exhibits synergistic anti‐tumor effects against TNBC. This study not only generates a powerful research tool to investigate the therapeutic potential of targeting eEF2K, but also provides a promising lead compound for developing novel drugs for the treatment of TNBC and other cancers.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Design and Characterization of a Novel eEF2K Degrader with Potent Therapeutic Efficacy Against Triple‐Negative Breast Cancer

Zhong,

Zhu,

Jiang

et al. 2023

Advanced Science

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“…[29] In the presence of � 250 μM NRX-1532, the affinity for β-Catenin and CRL1 β-TrCP was increased by a factor of 10, thus indicating that maximum cooperativity (α = 10) was reached at this concentration. [29] A similar strategy has also been employed to study the ternary complex formation orchestrated by IMiDs, [30] cyclin K MGs [24,31] (Figure 2), and aryl sulfonamides. [32] To determine values for binding and cooperativity, the classic bell-shaped curve observed in direct binding assays for PROTACs is difficult to deconvolute.…”

Section: Proximity-based Assays: Tr-fret and Alphascreenmentioning

confidence: 99%

“…Ternary complex formation in intact cells can be studied using technologies such as NanoBRET [21,41,[60][61][62] and NanoBiT, [54,63] as well as by cell imaging techniques (e. g. phase-shift live cell imaging [64][65] ). Furthermore, other approaches, namely coimmunoprecipitation, [66] chemo-proteomics, [31] cellular thermal shift assay (CETSA), [48,53,67] in-cell NMR, [68] and FP [69] can be used to address target engagement in lysates or in cells.…”

Section: In Cellulomentioning

confidence: 99%

“…[53] However, this technique relies on access to specific antibodies and it has limited sensitivity. Additional immunoblotting methods (e. g. capillary electrophoresis, [47] ELISA [66] and immunofluorescence [78] ) and mass spectrometry [20,24,31,67,72] have improved the quantification and sensitivity of determining protein levels. A key advantage of mass spectrometry analysis over immunoblotting methods is that it allows measurements of changes across the proteome.…”

Section: Monitoring Protein Degradation In Cellsmentioning

confidence: 99%

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Biophysical and Computational Approaches to Study Ternary Complexes: A ‘Cooperative Relationship’ to Rationalize Targeted Protein Degradation

2023

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Degraders have illustrated that compound-induced proximity to E3 ubiquitin ligases can prompt the ubiquitination and degradation of disease-relevant proteins. Hence, this pharmacology is becoming a promising alternative and complement to available therapeutic interventions (e. g., inhibitors). Degraders rely on protein binding instead of inhibition and, hence, they hold the promise to broaden the druggable proteome. Biophysical and structural biology approaches have been the cornerstone of understanding and rationalizing degraderinduced ternary complex formation. Computational models have now started to harness the experimental data from these approaches with the aim to identify and rationally help design new degraders. This review outlines the current experimental and computational strategies used to study ternary complex formation and degradation and highlights the importance of effective crosstalk between these approaches in the advancement of the targeted protein degradation (TPD) field. As our understanding of the molecular features that govern druginduced interactions grows, faster optimizations and superior therapeutic innovations for TPD and other proximity-inducing modalities are sure to follow.

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Frontiers in Medicinal Chemistry 2022 Goes Virtual

et al. 2022

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The Frontiers in Medicinal Chemistry (FiMC) meeting, which represents the largest international medicinal chemistry conference in Germany, took place from March 14th to 16th 2022 in a fully virtual format. Organized by the Division of Medicinal Chemistry of the German Chemical Society (GDCh) together with the Division of Pharmaceutical & Medicinal Chemistry of the German Pharmaceutical Society (DPhG) and a “local” organization committee from the University of Freiburg headed by Manfred Jung, the meeting brought together 271 participants from around 20 countries. The program included 33 lectures by leading scientists from industry and academia as well as early career investigators. 67 posters were presented in two poster sessions and with over 20.000 poster abstract downloads. The general organization and the time‐shift function were very much appreciated as demonstrated by almost 600 on‐demand contents retrieved. The online format fitted perfectly to bring together medicinal chemists from academia and industry across the globe.

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Publisher Correction: Rational discovery of molecular glue degraders via scalable chemical profiling

Cited by 6 publications

References 0 publications

Design and Characterization of a Novel eEF2K Degrader with Potent Therapeutic Efficacy Against Triple‐Negative Breast Cancer

Design and Characterization of a Novel eEF2K Degrader with Potent Therapeutic Efficacy Against Triple‐Negative Breast Cancer

Biophysical and Computational Approaches to Study Ternary Complexes: A ‘Cooperative Relationship’ to Rationalize Targeted Protein Degradation

Frontiers in Medicinal Chemistry 2022 Goes Virtual

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