Emerging and Re-emerging Warheads for Targeted Covalent Inhibitors: An Update

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(10), P. 7668 - 7758

Published: May 7, 2024

Covalent inhibitors and other types of covalent modalities have seen a revival in the past two decades, with variety new targeted drugs having been approved recent years. A key feature such molecules is an intrinsically reactive group, typically weak electrophile, which enables irreversible or reversible formation bond specific amino acid target protein. This often called "warhead", critical determinant ligand's activity, selectivity, general biological properties. In 2019, we summarized emerging re-emerging warhead chemistries to cysteine acids (Gehringer, M.; Laufer, S. A. J. Med. Chem. 62, 5673−5724; DOI: 10.1021/acs.jmedchem.8b01153). Since then, field has rapidly evolved. Here discuss progress on warheads made since our last Perspective their application medicinal chemistry chemical biology.

Language: Английский

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Traceless Peptide and Protein Modification via Rational Tuning of Pyridiniums

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(4), P. 2624 - 2633

Published: Jan. 19, 2024

Herein, we report a versatile reaction platform for tracelessly cleavable cysteine-selective peptide/protein modification. This offers highly tunable and predictable conjugation cleavage by rationally estimating the electron effect on nucleophilic halopyridiniums. Cleavable peptide stapling, antibody conjugation, enzyme masking/de-masking, proteome labeling were achieved based this facile pyridinium-thiol-exchange protocol.

Language: Английский

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Harnessing the 14-3-3 protein–protein interaction network

Current Opinion in Structural Biology, Journal Year: 2024, Volume and Issue: 86, P. 102822 - 102822

Published: April 28, 2024

Protein–protein interactions (PPIs) play a critical role in cellular signaling and represent interesting targets for therapeutic intervention. 14-3-3 proteins integrate many via PPIs are frequently implicated disease, making them intriguing drug targets. Here, we review the recent advances field. It will discuss roles within cell, elucidation of their expansive interactome, complex mechanisms that underpin function. In addition, significant development molecular glues target PPIs. particular, it focus on novel discovery methodologies have delivered selective, potent, drug-like molecules could open new avenues precision tools medicines.

Language: Английский

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14‐3‐3 Protein‐Protein Interactions: From Mechanistic Understanding to Their Small‐Molecule Stabilization

ChemBioChem, Journal Year: 2024, Volume and Issue: 25(14)

Published: May 13, 2024

Abstract Protein‐protein interactions (PPIs) are of utmost importance for maintenance cellular homeostasis. Herein, a central role can be found 14‐3‐3 proteins. These hub‐proteins known to bind hundreds interaction partners, thereby regulating their activity, localization, and/or stabilization. Due ability large variety client proteins, studies protein complexes flourished over the last decades, aiming gain greater molecular understanding these and in health disease. Because crucial within cell, recognized as highly interesting therapeutic targets, encouraging discovery small molecule modulators PPIs. We discuss various examples 14‐3‐3‐mediated regulation its binding partners on mechanistic level, highlighting versatile multi‐functional cell. Furthermore, an overview is given development stabilizers complexes, from initially used natural products fragment‐based approaches. show potential PPI novel agents drug tool compounds 14‐3‐3‐based regulation.

Language: Английский

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Structure-Based Optimization of Covalent, Small-Molecule Stabilizers of the 14-3-3σ/ERα Protein–Protein Interaction from Nonselective Fragments

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(37), P. 20328 - 20343

Published: Sept. 7, 2023

The stabilization of protein-protein interactions (PPIs) has emerged as a promising strategy in chemical biology and drug discovery. identification suitable starting points for stabilizing native PPIs their subsequent elaboration into selective potent molecular glues lacks structure-guided optimization strategies. We have previously identified disulfide fragment that stabilized the hub protein 14-3-3σ bound to several its clients, including ERα C-RAF. Here, we show structure-based nonselective toward highly small-molecule stabilizers 14-3-3σ/ERα complex. more elaborated glues, example, no 14-3-3σ/C-RAF up 150 μM compound. Orthogonal biophysical assays, mass spectrometry fluorescence anisotropy, were used establish structure-activity relationships. binding modes 37 compounds elucidated with X-ray crystallography, which further assisted concomitant optimization. By targeting specific amino acids interface locking conformation spirocycle, optimized covalent stabilizer 181 achieved potency, cooperativity, selectivity similar natural product Fusicoccin-A. This case study showcases value addressing structure, kinetics, cooperativity glue development.

Language: Английский

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The expanding repertoire of covalent warheads for drug discovery

Drug Discovery Today, Journal Year: 2023, Volume and Issue: 28(12), P. 103799 - 103799

Published: Oct. 13, 2023

Language: Английский

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Tracking the mechanism of covalent molecular glue stabilization using native mass spectrometry

Chemical Science, Journal Year: 2023, Volume and Issue: 14(24), P. 6756 - 6762

Published: Jan. 1, 2023

Molecular glues are powerful tools for the control of protein-protein interactions. Yet, mechanisms underlying multi-component protein complex formation remain poorly understood. Native mass spectrometry (MS) detects multiple species simultaneously, providing an entry to elucidate these mechanisms. Here, first time, covalent molecular glue stabilization was kinetically investigated by combining native MS with biophysical and structural techniques. This approach elucidated stoichiometry a protein-ligand complex, assembly order, contributions versus non-covalent binding events that govern activity. Aldehyde-based activity is initially regulated cooperative binding, followed slow ligation, further enhancing stabilization. study provides framework investigate small molecule ligation informs (covalent) development.

Language: Английский

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Ubiquitin E3 ligases assisted technologies in protein degradation: Sharing pathways in neurodegenerative disorders and cancer

Ageing Research Reviews, Journal Year: 2024, Volume and Issue: 96, P. 102279 - 102279

Published: March 22, 2024

Language: Английский

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The Structure Determination of Organic Molecules by Co-crystallization of Anthracene-Based Crystallization Chaperone

ACS Materials Letters, Journal Year: 2023, Volume and Issue: 5(10), P. 2673 - 2682

Published: Aug. 31, 2023

Single crystal X-ray diffraction is considered to be a highly reliable method for determining the molecular structures and absolute conformation at atomic level, but this technique limited application of oily organic molecules that are difficult crystallize. Here, we report an anthracene-based crystallization chaperone TMAPA overcome above limitation, where 56 various guest were co-crystallized with in solvent. As result, 51 high-resolution co-crystal (chiral or achiral) determined short time so refined can readily determined. Importantly, anthracene moieties introduced structure could not only extend length arms increase size pores also adaptively adopt different conformations leading efficient capture molecule during co-crystallization process. It expected work will open up new possibilities structural identification determination unknown molecules.

Language: Английский

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Screening for molecular glues – Challenges and opportunities

SLAS DISCOVERY, Journal Year: 2023, Volume and Issue: 29(2), P. 100136 - 100136

Published: Dec. 15, 2023

Molecular glues are small molecules, typically smaller than PROTACs, and usually with improved physicochemical properties that aim to stabilise the interaction between two proteins. Most often this approach is used improve or induce an target E3 ligase, but other interactions which increase activity inhibit binding a natural effector have also been demonstrated. This review will describe effects of induced proximity, discuss current methods identify molecular introduce approaches could be adapted for glue screening.

Language: Английский

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