“…However, with the addition of the (+)-JQ1 enantiomer, BRD4 bromo and CENP-B become significantly more enriched, indicating that (+)-JQ1 stabilises the BRD4-JQ1-CENP-B-DNA complex in vitro . The stabilisation of a low-affinity interaction is one of the defining properties of a rare class of drugs called molecular-glues, which enable gain-of-function interactions that can target previously undruggable pathways 20, 21 , and our evidence suggests that JQ1 is the first centromere-targeting drug via this mechanism-of-action.…”
Section: Introductionmentioning
confidence: 83%
“…A molecular-glue mechanism-of-action enables JQ1 to stabilises a direct protein- protein interaction between BRD4 and the centromere DNA binding protein CENP-B. The identification of molecular-glues is rare, but each new example opens up the possibility of targeting previously undruggable pathways 20, 21 . Future optimisation of JQ1 structure could form the basis of a new class of centromere drugs targeting chromosome segregation, a process which is important only in dividing cells.…”
Section: Discussionmentioning
confidence: 99%
“…We show that JQ1 stabilises a protein-protein interaction between BRD4 and the centromere DNA binding protein CENP-B 19 , identifying the first case of a drug directly targeting centromeric chromatin. Drugs that stabilise protein-protein interactions, called molecular-glues, often accentuate one particular function of a protein 20, 21 . CENP-B removal reveals that JQ1 treatment stabilises centromere cohesion, demonstrating a direct effect of the BRD4-JQ1-CENP-B interaction on centromeric cohesion.…”
Centromeres are essential for cell proliferation and a promising target for anti-cancer therapies, yet no drugs have been identified that specifically target centromeric chromatin. To identify candidates, we analysed chromatin proteins at repetitive loci using a novel big-data approach and discovered the bromodomain protein BRD4 localises to centromeres, a localisation enhanced by the bromodomain inhibitor JQ1. While bromodomain inhibitors typically prevent BRD4 from binding chromatin, we found that JQ1 stabilises an interaction between BRD4 and the centromere protein CENP-B. Degradation of BRD4 caused centromere cohesion defects, whereas JQ1-treatment preserved centromere structure in a CENP-B dependent manner. Strikingly, JQ1-resistant cells became reliant on CENP-B for proliferation. Our results identify a non-canonical role for BRD4 in centromere cohesion and establish JQ1 as a molecular-glue targeting centromeric chromatin.
“…However, with the addition of the (+)-JQ1 enantiomer, BRD4 bromo and CENP-B become significantly more enriched, indicating that (+)-JQ1 stabilises the BRD4-JQ1-CENP-B-DNA complex in vitro . The stabilisation of a low-affinity interaction is one of the defining properties of a rare class of drugs called molecular-glues, which enable gain-of-function interactions that can target previously undruggable pathways 20, 21 , and our evidence suggests that JQ1 is the first centromere-targeting drug via this mechanism-of-action.…”
Section: Introductionmentioning
confidence: 83%
“…A molecular-glue mechanism-of-action enables JQ1 to stabilises a direct protein- protein interaction between BRD4 and the centromere DNA binding protein CENP-B. The identification of molecular-glues is rare, but each new example opens up the possibility of targeting previously undruggable pathways 20, 21 . Future optimisation of JQ1 structure could form the basis of a new class of centromere drugs targeting chromosome segregation, a process which is important only in dividing cells.…”
Section: Discussionmentioning
confidence: 99%
“…We show that JQ1 stabilises a protein-protein interaction between BRD4 and the centromere DNA binding protein CENP-B 19 , identifying the first case of a drug directly targeting centromeric chromatin. Drugs that stabilise protein-protein interactions, called molecular-glues, often accentuate one particular function of a protein 20, 21 . CENP-B removal reveals that JQ1 treatment stabilises centromere cohesion, demonstrating a direct effect of the BRD4-JQ1-CENP-B interaction on centromeric cohesion.…”
Centromeres are essential for cell proliferation and a promising target for anti-cancer therapies, yet no drugs have been identified that specifically target centromeric chromatin. To identify candidates, we analysed chromatin proteins at repetitive loci using a novel big-data approach and discovered the bromodomain protein BRD4 localises to centromeres, a localisation enhanced by the bromodomain inhibitor JQ1. While bromodomain inhibitors typically prevent BRD4 from binding chromatin, we found that JQ1 stabilises an interaction between BRD4 and the centromere protein CENP-B. Degradation of BRD4 caused centromere cohesion defects, whereas JQ1-treatment preserved centromere structure in a CENP-B dependent manner. Strikingly, JQ1-resistant cells became reliant on CENP-B for proliferation. Our results identify a non-canonical role for BRD4 in centromere cohesion and establish JQ1 as a molecular-glue targeting centromeric chromatin.
“…Our study shows that meroterpenoids bearing dialdehyde phloroglucinol core may serve as covalent protein dimerizers and molecular glues through a unique mechanism of action that targets lysine residues within proteins. Given the burgeoning interest in chemical inducers of dimerization and molecular glues that modulate protein function through induced aggregation as a therapeutic strategy, 99 these natural products could function as versatile tools for surveying protein aggregation and homo-and heterodimerization in the human proteome. Future efforts will leverage the chemical proteomics strategy coupled with size exclusion chromatography 117 to assess the global impact of phloroglucinol meroterpenoids on protein complexes in cells, thereby elucidating the functional consequences and identifying potential neosubstrates.…”
Natural products perennially serve
as prolific sources of drug
leads and chemical probes, fueling the development of numerous therapeutics.
Despite their scarcity, natural products that modulate protein function
through covalent interactions with lysine residues hold immense potential
to unlock new therapeutic interventions and advance our understanding
of the biological processes governed by these modifications. Phloroglucinol
meroterpenoids constitute one of the most expansive classes of natural
products, displaying a plethora of biological activities. However,
their mechanism of action and cellular targets have, until now, remained
elusive. In this study, we detail the concise biomimetic synthesis,
computational mechanistic insights, physicochemical attributes, kinetic
parameters, molecular mechanism of action, and functional cellular
targets of several phloroglucinol meroterpenoids. We harness synthetic
clickable analogues of natural products to probe their disparate proteome-wide
reactivity and subcellular localization through in-gel fluorescence
scanning and cell imaging. By implementing sample multiplexing and
a redesigned lysine-targeting probe, we streamline a quantitative
activity-based protein profiling, enabling the direct mapping of global
reactivity and ligandability of proteinaceous lysines in human cells.
Leveraging this framework, we identify numerous lysine–meroterpenoid
interactions in breast cancer cells at tractable protein sites across
diverse structural and functional classes, including those historically
deemed undruggable. We validate that phloroglucinol meroterpenoids
perturb biochemical functions through stereoselective and site-specific
modification of lysines in proteins vital for breast cancer metabolism,
including lipid signaling, mitochondrial respiration, and glycolysis.
These findings underscore the broad potential of phloroglucinol meroterpenoids
for targeting functional lysines in the human proteome.
“… 192 , 193 Notably, LSN3160440 interacts with GLP-1 and acts as a molecular glue. 194 The 2,6-dichloro-3-methoxyl phenyl moiety of LSN3160440 forms van der Waals interactions with Phe12 GLP-1 , Val16 GLP-1 and Leu20 GLP-1 simultaneously. Fig.…”
Section: Advances In Gpcr Drug Discoverymentioning
G protein-coupled receptors (GPCRs), the largest family of human membrane proteins and an important class of drug targets, play a role in maintaining numerous physiological processes. Agonist or antagonist, orthosteric effects or allosteric effects, and biased signaling or balanced signaling, characterize the complexity of GPCR dynamic features. In this study, we first review the structural advancements, activation mechanisms, and functional diversity of GPCRs. We then focus on GPCR drug discovery by revealing the detailed drug-target interactions and the underlying mechanisms of orthosteric drugs approved by the US Food and Drug Administration in the past five years. Particularly, an up-to-date analysis is performed on available GPCR structures complexed with synthetic small-molecule allosteric modulators to elucidate key receptor-ligand interactions and allosteric mechanisms. Finally, we highlight how the widespread GPCR-druggable allosteric sites can guide structure- or mechanism-based drug design and propose prospects of designing bitopic ligands for the future therapeutic potential of targeting this receptor family.
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