Designing Selective Drug-like Molecular Glues for the Glucocorticoid Receptor/14-3-3 Protein–Protein Interaction

Pallesen, Jakob; Munier, Claire C; Bosica, Francesco; Andrei, Sebastian A.; Edman, K. A. P.; Gunnarsson, Anders; Sala, Giuseppina La; Putra, Okky Dwichandra; Srdanović, Sonja; Wilson, Andrew J.; Wissler, Lisa; Ottmann, C.; Perry, Matthew W. D.; O’Mahony, Gavin

doi:10.1021/acs.jmedchem.2c01635

Cited by 7 publications

(3 citation statements)

References 40 publications

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“…[119] Structure-activity-relationship (SAR) studies on pyrrolidone1 provided more potent 14-3-3/ PMA2 molecular glues [120] which, later on, also showed to stabilize the 14-3-3/ERα, 14-3-3/CaMKK2, and 14-3-3/GR protein complexes (Figure 6a). [121,122] Since the identification of the pyrrolidones, more screening campaigns were performed to identify stabilizers for various 14-3-3 PPIs. For example, a virtual screening campaign led to the identification of phosphonatebased stabilizers that bind in the 14-3-3 phospho-accepting pocket thereby stabilizing the binding of the phosphorylationindependent 14-3-3 binder ChREBP (Figure 6b).…”

Section: Compound and Fragment Screening To Identify 14-3-3 Ppi Stabi...mentioning

confidence: 99%

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

Somsen,

Cossar,

Arkin

et al. 2024

ChemBioChem

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

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Section: Compound and Fragment Screening To Identify 14-3-3 Ppi Stabi...mentioning

confidence: 99%

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

Somsen,

Cossar,

Arkin

et al. 2024

ChemBioChem

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“…Recent examples of synthetic non-covalent 14-3-3 PPI Molecular Glues highlight the potential of further exploring strategies for chemical maturation of noncovalent fragment libraries. [19] Here, we performed non-covalent fragment extension as a previously non-addressed concept for 14-3-3 PPI stabilization. Specifically, in this fragment extension approach we explored the potential to build off from a non-covalent amidine substituted thiophene fragment (Figure 1B).…”

Section: Introductionmentioning

confidence: 99%

Discovery of 14‐3‐3 PPI Stabilizers by Extension of an Amidine‐Substituted Thiophene Fragment

Wu,

Centorrino,

Guillory

et al. 2023

ChemBioChem

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Protein‐protein interaction (PPI) modulation is a promising approach in drug discovery with the potential to expand the ‘druggable’ proteome and develop new therapeutic strategies. While there have been significant advancements in methodologies for developing PPI inhibitors, there is a relative scarcity of literature describing the ‘bottom‐up’ development of PPI stabilizers (Molecular Glues). The hub protein 14‐3‐3 and its interactome provide an excellent platform for exploring conceptual approaches to PPI modulation, including evolution of chemical matter for Molecular Glues. In this study, we employed a fragment extension strategy to discover stabilizers for the complex of 14‐3‐3 protein and an Estrogen Receptor alpha‐derived peptide (ERα). A focused library of analogues derived from an amidine‐substituted thiophene fragment enhanced the affinity of the 14‐3‐3/ERα complex up to 6.2‐fold. Structure‐activity relationship (SAR) analysis underscored the importance of the newly added, aromatic side chain with a certain degree of rigidity. X‐ray structural analysis revealed a unique intermolecular π–π stacking binding mode of the most active analogues, resulting in the simultaneous binding of two molecules to the PPI binding pocket. Notably, analogue 11 displayed selective stabilization of the 14‐3‐3/ERα complex.

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“…Compound 2 is a trisubstituted pyrrolinone harboring the crucial salicylic acid moiety of 1 , a nitrophenyl residue at the 5-position and a benzoyl substituent at the 4-position. Compound 2 , as well as the series of trisubstituted pyrrolinones, was previously reported as a stabilizer of the protein–protein interaction (PPI) between 14-3-3 protein and the plasma membrane protein H + -ATPase 2 (PMA2) of plants. − The EMSA assay separates the protein–RNA complex of LIN28 and let-7 from unbound let-7 in nondenaturing electrophoresis. The RNA was detected by its fluorophore label, allowing a visual readout and a robust throughput.…”

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confidence: 99%

N-Biphenyl Pyrrolinones and Dibenzofurans as RNA-Binding Protein LIN28 Inhibitors Disrupting the LIN28–Let-7 Interaction

Borgelt,

Hohnen,

Pallesen

et al. 2023

ACS Med. Chem. Lett.

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The RNA-binding protein LIN28 is a regulator of miRNA let-7 biogenesis. Inhibitors of LIN28 are highly sought after given the central role that LIN28 plays in tumorigenesis and development of cancer stem cells as well as LIN28's association with poor clinical prognosis. Although LIN28 inhibitors of different scaffolds have been reported, the potential of most LIN28 inhibiting small molecules was not fully explored since very limited structure−activity relationship (SAR) studies have been performed. We previously identified trisubstituted pyrrolinones as a new class of LIN28 inhibitors disrupting the LIN28−let-7 interaction. Here, we performed extensive SAR by evaluating 95 small molecules and identified new trisubstituted pyrrolinones featuring either an N-biphenyl or Ndibenzofuran substituent, overthrowing the existing conclusion that a salicylic acid moiety is indispensable for activity. Exchange of the negatively charged salicylic acid moiety in LIN28 inhibitors with a heterocyclic substituent is beneficial for membrane permeability, leading to increased activity in a cellular assay, and will potentially reduce toxicity.

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Designing Selective Drug-like Molecular Glues for the Glucocorticoid Receptor/14-3-3 Protein–Protein Interaction

Cited by 7 publications

References 40 publications

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

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

Discovery of 14‐3‐3 PPI Stabilizers by Extension of an Amidine‐Substituted Thiophene Fragment

N-Biphenyl Pyrrolinones and Dibenzofurans as RNA-Binding Protein LIN28 Inhibitors Disrupting the LIN28–Let-7 Interaction

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