Identification of 2,4,5-trisubstituted-2,4-dihydro-3H-1,2,4-triazol-3-one-based small molecules as selective BRD9 binders

Colarusso, Ester; Ceccacci, Sara; Monti, Maria Chiara; Gazzillo, Erica; Giordano, Assunta; Chini, Maria Giovanna; Ferraro, Maria Grazia; Piccolo, Marialuisa; Ruggiero, Dafne; Irace, Carlo; Terracciano, Stefania; Bruno, Ines; Bifulco, Giuseppe; Lauro, Gianluigi

doi:10.1016/j.ejmech.2022.115018

Cited by 8 publications

(7 citation statements)

References 40 publications

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“…A donor solution (50 μM) was prepared by diluting 5 mM TatA stock solutions using phosphate-buffered saline (PBS, pH 7.4). The experiments were performed as reported in Colarusso et al (2023 ). The permeability value Log Pe was determined.…”

Section: Methodsmentioning

confidence: 99%

Targeting phosphoglycerate kinases by tatridin A, a natural sesquiterpenoid endowed with anti-cancer activity, using a proteomic platform

Ferraro,

Voli,

Mozzicafreddo

et al. 2023

Front. Mol. Biosci.

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Tatridin A (TatA) is a germacrane sesquiterpenoid containing one E-double bond and one Z-double bond in its 10-membered ring, which is fused to a 3-methylene-dihydrofuran-2-one moiety. Tatridin A bioactivity has been poorly investigated despite its interesting chemical structure. Here, a functional proteomic platform was adapted to disclose its most reliable targets in leukemia monocytic cells, and phosphoglycerate kinases were recognized as the most affine enzymes. Through a combination of limited proteolysis and molecular docking, it has been discovered that tatridin A interacts with the active domains of phosphoglycerate kinase 1, altering its hinge region, and it can be accountable for tatridin A inhibition potency on enzyme activity. A more detailed tatridin A biological profile showed that it is also fully active against gastric cancer cells, downregulating the mRNA levels of chemokine receptor 4 and β-catenin and inhibiting the invasiveness of living KATO III cells as a direct consequence of phosphoglycerate kinase 1 antagonism.

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Section: Methodsmentioning

confidence: 99%

Targeting phosphoglycerate kinases by tatridin A, a natural sesquiterpenoid endowed with anti-cancer activity, using a proteomic platform

Ferraro,

Voli,

Mozzicafreddo

et al. 2023

Front. Mol. Biosci.

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“…Recently [ 47 ], employing computational methodologies, selective BRD9 inhibitors with a 2,4,5-trisubstituted-2,4-dihydro-3 H -1,2,4-triazol-3-one chemical core were identified ( Figure 20 ). Initially, six differently functionalized cores were virtually examined to assess their potential to bind the target.…”

Section: Brd9 Bindersmentioning

confidence: 99%

“…An E3 ubiquitin ligase ligand is linked to a protein-of-interest ligand (also known as a “warhead”) by a linker of varying lengths and chemical composition [ 53 ]. BRD9 inhibitors often demonstrate poor cellular activity [ 47 ] despite strong activity on the protein, attributable to BRD9’s involvement in the SWI/SNF complex. Consequently, developing PROTACs from these known inhibitors may prove crucial in enhancing their biological efficacy on the target of interest, offering promising avenues for therapeutic intervention.…”

Section: Brd9 Proteolysis Targeting Chimeras (Protacs)mentioning

confidence: 99%

“…Intriguingly, these compounds did not demonstrate significant binding to BRD4(BD1), establishing them as novel BRD9 binders with promising selective behavior. Recently [47], employing computational methodologies, selective BRD9 inhibitors with a 2,4,5-trisubstituted-2,4-dihydro-3H-1,2,4-triazol-3-one chemical core were identified (Figure 20). Initially, six differently functionalized cores were virtually examined to assess their potential to bind the target.…”

Section: -Methylquinazolin-4(3h)-one Analogsmentioning

confidence: 99%

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Identification and Development of BRD9 Chemical Probes

Colarusso,

Chini,

Bifulco

et al. 2024

Pharmaceuticals

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The development of BRD9 inhibitors involves the design and synthesis of molecules that can specifically bind the BRD9 protein, interfering with the function of the chromatin-remodeling complex ncBAF, with the main advantage of modulating gene expression and controlling cellular processes. Here, we summarize the work conducted over the past 10 years to find new BRD9 binders, with an emphasis on their structure–activity relationships, efficacies, and selectivities in preliminary studies. BRD9 is expressed in a variety of cancer forms, hence, its inhibition holds particular significance in cancer research. However, it is crucial to note that the expanding research in the field, particularly in the development of new degraders, may uncover new therapeutic potentials.

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“…Recently, driven by the need to create a reliable filter to screen large compound libraries, our group presented a new strategy to extract the pharmacophore features from small molecules cocrystallized with their target. − Briefly, in the effort to develop new binders for the epigenetic reader bromodomain-containing protein 9 (BRD9) and soluble epoxide hydrolase (sEH), we decided to consider all of the available crystal structures containing a ligand for the development of a tailored pharmacophore that would trace the actual binding mode of the bioactive molecules. The benefits deriving from the integration between the intrinsic chemical features of the ligands and the way they are oriented inside the pocket were immediately visible, leading to the selection of very promising compounds. − However, the whole procedure was still laborious and required several days of work to develop a few hypotheses. Therefore, the desire to exploit this new powerful filter in a routine virtual screening campaign urged us to find a way to reduce the required time.…”

Section: Introductionmentioning

confidence: 99%

PharmaCore: The Automatic Generation of 3D Structure-Based Pharmacophore Models from Protein/Ligand Complexes

De Vita,

Colarusso,

Chini

et al. 2024

J. Chem. Inf. Model.

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In this work, we present PharmaCore: a new, completely automatic workflow aimed at generating three-dimensional (3D) structure-based pharmacophore models toward any target of interest. The proposed approach relies on using cocrystallized ligands to create the input files for generating the pharmacophore hypotheses, integrating not only the three-dimensional structural information on the ligand but also data concerning the binding mode of these molecules put in the protein cavity. We developed a Python library that, starting from the specific UniProt ID of the protein under investigation as the only element that requires user intervention, subsequently collects and aligns the corresponding structures bearing a known ligand in a fully automated fashion, bringing them all into the same coordinate system. The protocol includes a final phase in which the aligned small molecules are used to produce the pharmacophore hypotheses directly onto the protein structure using a specific software, e.g., Phase (Schrodinger LLC). To validate the entire procedure and highlight the possible applications in the field of drug discovery and repositioning, we first generated pharmacophores for soluble epoxide hydrolase (sEH) and compared with already-published ones. Then, we reproduced the binding profile of a reported selective binder of ATAD2 bromodomain (AM879), testing it against a panel of 1741 pharmacophores related to 16 epigenetic proteins and automatically generated with PharmaCore, finally disclosing putative unprecedented off-targets. The computational predictions were successfully validated with AlphaScreen assays, highlighting the applicability of the proposed workflow in drug discovery and repositioning. Finally, the process was also validated on tankyrase 2 and SARS-CoV-2 M Pro , confirming the robustness of PharmaCore.

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Identification of 2,4,5-trisubstituted-2,4-dihydro-3H-1,2,4-triazol-3-one-based small molecules as selective BRD9 binders

Cited by 8 publications

References 40 publications

Targeting phosphoglycerate kinases by tatridin A, a natural sesquiterpenoid endowed with anti-cancer activity, using a proteomic platform

Targeting phosphoglycerate kinases by tatridin A, a natural sesquiterpenoid endowed with anti-cancer activity, using a proteomic platform

Identification and Development of BRD9 Chemical Probes

PharmaCore: The Automatic Generation of 3D Structure-Based Pharmacophore Models from Protein/Ligand Complexes

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