Structure-based virtual screening towards the discovery of novel FOXM1 inhibitors

2021 ◽  
Author(s):  
Zhuo-Song Xie ◽  
Zi-Ying Zhou ◽  
Lian-Qi Sun ◽  
Hong Yi ◽  
Si-Tu Xue ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Virtual Screening ◽  
Mouse Model ◽  
Small Molecules ◽  
Antiproliferative Activity ◽  
Binding Sites ◽  
Specific Inhibitor ◽  
Activity Analysis ◽  
Computer Aided Drug Design

Aim: Given the importance of FOXM1 in the treatment of ovarian cancer, we aimed to identify an excellent specific inhibitor and examined its underlying therapeutic effect. Materials & methods: The binding statistics for FDI-6 with FOXM1 were calculated through computer-aided drug design (CADD). We selected XST-119 through virtual screening, performed surface plasmon resonance and in vitro cell antiproliferative activity analysis and evaluated its antitumor efficacy in a mouse model. Results: XST-119 had significantly higher affinity for FOXM1 and antiproliferative activity than FDI-6. XST-119 had a definite inhibitory activity in a xenograft mouse model. Conclusion: We identified XST-119, a FOXM1 inhibitor, with better efficacy for treatment of ovarian cancer. FOXM1 binding sites for small molecules are also highlighted, which may provide the foundation for further drug discovery.

127 TREATMENTS WITH DIVERSE ENDOCRINE-DISRUPTING CHEMICALS RESULTED IN THE INHIBITION OF OVARIAN TUMOR PROGRESSION VIA INTERRUPTION OF TRANSFORMING GROWTH FACTOR-β IN IN VITRO AND XENOGRAFTED MOUSE MODELS

2014 ◽  
Vol 26 (1) ◽  
pp. 177
Author(s):  
H.-R. Lee ◽  
R.-E. Go ◽  
K.-C. Choi
Keyword(s):  
Ovarian Cancer ◽  
Growth Factor ◽  
Mouse Model ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Mouse Models ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Xenograft Mouse Model

Activated oestrogen receptor (ER) signaling pathway by 17β-estadiol (E2) appeared to suppress transforming growth factor β (TGF-β) signaling pathway by cross-talk with TGF-β components in ER-positive cancer cells. In this study, we further examined the inhibitory effects of alkylphenols, including 4-nonylphenol (NP), 4-otylphenol (OP), bisphenol A (BPA), and benzophenon-1 (BP-1), in TGF-β signaling pathway. The transcriptional and translational levels of TGF-β-related genes were examined by reverse-transcription PCR (RT-PCR), Western blotting analysis in xenografted mouse models of ovarian cancer BG-1 cells. The NP, OP, and BPA induced the expression of snoN, a TGF-β pathway inhibitor. Treatment with NP, BPA, and BP-1 resulted in decreased phosphorylation of Smad3, a downstream target of TGF-β. With these 2 effects, NP and BPA stimulated the proliferation of BG-1 cells via inhibition of the TGF-β signaling pathway. In a xenograft mouse model, transplanted BG-1 ovarian cancer cells showed significantly decreased phosphorylation of Smad3 and increased expression of snoN in the ovarian tumour masses following treatment with E2, NP, or BPA. In parallel with an in vitro model, the expressions of TGF-β signaling pathway were similarly regulated by NP or BPA in a xenograft mouse model, revealing consistent results. Taken together, these results support that NP and BPA may cause the disruption of the TGF-β signaling pathway and increase the risk of oestrogen-dependent cancers such as ovarian cancer. This work was supported by a grant from the Next-Generation BioGreen 21 Program (No. PJ009599), Rural Development Administration, Republic of Korea.

scholarly journals Genomic targeting of epigenetic probes using a chemically tailored Cas9 system

2017 ◽  
Vol 114 (4) ◽  
pp. 681-686 ◽  
Author(s):  
Glen P. Liszczak ◽  
Zachary Z. Brown ◽  
Samuel H. Kim ◽  
Rob C. Oslund ◽  
Yael David ◽  
...  
Keyword(s):  
Dna Binding ◽  
Chemical Synthesis ◽  
Small Molecules ◽  
Small Molecule ◽  
Binding Sites ◽  
Dna Binding Protein ◽  
Dna Binding Proteins ◽  
Live Cells ◽  
Binding Partners

Recent advances in the field of programmable DNA-binding proteins have led to the development of facile methods for genomic localization of genetically encodable entities. Despite the extensive utility of these tools, locus-specific delivery of synthetic molecules remains limited by a lack of adequate technologies. Here we combine the flexibility of chemical synthesis with the specificity of a programmable DNA-binding protein by using protein trans-splicing to ligate synthetic elements to a nuclease-deficient Cas9 (dCas9) in vitro and subsequently deliver the dCas9 cargo to live cells. The versatility of this technology is demonstrated by delivering dCas9 fusions that include either the small-molecule bromodomain and extra-terminal family bromodomain inhibitor JQ1 or a peptide-based PRC1 chromodomain ligand, which are capable of recruiting endogenous copies of their cognate binding partners to targeted genomic binding sites. We expect that this technology will allow for the genomic localization of a wide array of small molecules and modified proteinaceous materials.

scholarly journals Discovery of a specific inhibitor of human GLUT5 by virtual screening and in vitro transport evaluation

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Alayna M. George Thompson ◽  
Oleg Ursu ◽  
Petr Babkin ◽  
Cristina V. Iancu ◽  
Alex Whang ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Specific Inhibitor

scholarly journals Cepharanthine Blocks Presentation of Thyroid and Islet Peptides in a Novel Humanized Autoimmune Diabetes and Thyroiditis Mouse Model

2021 ◽  
Vol 12 ◽  
Author(s):  
Cheuk Wun Li ◽  
Roman Osman ◽  
Francesca Menconi ◽  
Larissa C. Faustino ◽  
Kookjoo Kim ◽  
...  
Keyword(s):  
T Cell ◽  
Mouse Model ◽  
Small Molecules ◽  
T Cell Activation ◽  
Cell Activation ◽  
Therapeutic Potential ◽  
Autoimmune Diabetes ◽  
Autoimmune Response ◽  
Hla Dr3

Autoimmune polyglandular syndrome type 3 variant (APS3v) refers to an autoimmune condition in which both type 1 diabetes (T1D) and autoimmune thyroiditis (AITD) develop in the same individual. HLA-DR3 confers the strongest susceptibility to APS3v. Previously we reported a unique amino acid signature pocket that predisposes to APS3v. We found that this pocket is flexible and can trigger APS3v by presenting both thyroid (Tg.1571, TPO.758) and islet (GAD.492) peptides to induce autoimmune response. We hypothesized that blocking the specific APS3v-HLA-DR3 pocket from presenting thyroid/islet antigens can block the autoimmune response in APS3v. To test this hypothesis we performed a virtual screen of small molecules blocking APS3v-HLA-DR3, and identified 11 small molecules hits that were predicted to block APS3v-HLA-DR3. Using the baculovirus-produced recombinant APS3v-HLA-DR3 protein we tested the 11 small molecules in an in vitro binding assay. We validated 4 small molecule hits, S9, S5, S53 and S15, that could block the APS3v-HLA-DR3 pocket in vitro. We then developed a novel humanized APS3v mouse model induced by co-immunizing a peptide mix of Tg.1571, TPO.758 and GAD.492. The immunized mice developed strong T-cell and antibody responses to the thyroid/islet peptides, as well as mouse thyroglobulin. In addition, the mice showed significantly lower free T4 levels compared to controls. Using the APS3v mouse model, we showed that one of the 4 small molecules, Cepharanthine (S53), blocked T-cell activation by thyroid/islet peptides ex vivo and in vivo. These findings suggested Cepharanthine may have a therapeutic potential in APS3v patients carrying the specific APS3v-HLA-DR3 pocket.

scholarly journals Glideosomal GAP50 binders that inhibit invasion and restrict malaria parasite in vitro and in vivo

2021 ◽  
Author(s):  
Prakhar Agrawal ◽  
Surekha Kumari ◽  
Upendra Sharma ◽  
Dinkar Sahal
Keyword(s):  
Mouse Model ◽  
Small Molecules ◽  
Malaria Parasite ◽  
Drug Combinations ◽  
Antiplasmodial Activity ◽  
Modern World ◽  
Anchor Protein

Abstract Malaria continues to be a killer disease even in the modern world. Vaccines and drugs have a lot to learn from the malaria parasite before they can be successful. Here, using a filter for glideosomal anchor protein PfGAP50, we have explored a plethora of small molecules to shortlist eight GAP50 binders with promising antiplasmodial activity (IC50 < 3 µM) that are also highly selective. Of these, Hayatinin, Bedaquiline, MMV688271, Curine, and Brilacidin with PfINDO IC50 ≤ 1 µM were found to stall merozoites invasion by inhibiting IMC formation besides increasing ROS levels in trophozoites. Bedaquiline loaded healthy RBCs showed prophylactic ability to prevent intraerythrocytic development of malaria parasite. Synergistic activities with ΣFIC values as low as 0.22 (Curine and Artemisinin) or 0.37 (Bedaquiline and Artemisinin) augur well for the development of drug combinations to combat malaria effectively. Interestingly, orally delivered Bedaquiline (50 mg/Kg b. wt.) showed substantial suppression of parasitemia in the mouse model of malaria.

scholarly journals Structural-based virtual screening and in vitro assays for small molecules inhibiting the feline coronavirus 3CL protease as a surrogate platform for coronaviruses

2020 ◽  
Vol 182 ◽  
pp. 104927
Author(s):  
Sirin Theerawatanasirikul ◽  
Chih Jung Kuo ◽  
Nanthawan Phecharat ◽  
Jullada Chootip ◽  
Chalermpol Lekcharoensuk ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Small Molecules ◽  
In Vitro Assays ◽  
3Cl Protease ◽  
Feline Coronavirus

scholarly journals Modulating protein activity using tethered ligands with mutually exclusive binding sites

2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Alberto Schena ◽  
Rudolf Griss ◽  
Kai Johnsson
Keyword(s):  
Small Molecules ◽  
Binding Sites ◽  
Protein A ◽  
Living Cells ◽  
Protein Activity ◽  
Research Areas ◽  
Specific Effector ◽  
Tethered Ligands ◽  
General Method

Abstract The possibility to design proteins whose activities can be switched on and off by unrelated effector molecules would enable applications in various research areas, ranging from biosensing to synthetic biology. We describe here a general method to modulate the activity of a protein in response to the concentration of a specific effector. The approach is based on synthetic ligands that possess two mutually exclusive binding sites, one for the protein of interest and one for the effector. Tethering such a ligand to the protein of interest results in an intramolecular ligand–protein interaction that can be disrupted through the presence of the effector. Specifically, we introduce a luciferase controlled by another protein, a human carbonic anhydrase whose activity can be controlled by proteins or small molecules in vitro and on living cells, and novel fluorescent and bioluminescent biosensors.

Virtual screening of small molecules databases for discovery of novel PARP-1 inhibitors: combination of in silico and in vitro studies

2016 ◽  
Vol 35 (9) ◽  
pp. 1899-1915 ◽  
Author(s):  
Ramin Ekhteiari Salmas ◽  
Ayhan Unlu ◽  
Muhammet Bektaş ◽  
Mine Yurtsever ◽  
Mert Mestanoglu ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Small Molecules ◽  
In Silico ◽  
In Vitro Studies ◽  
Parp 1

scholarly journals A cell-based screening method using an intracellular antibody for discovering small molecules targeting the translocation protein LMO2

2021 ◽  
Vol 7 (15) ◽  
pp. eabg1950
Author(s):  
Nicolas Bery ◽  
Carole J.R. Bataille ◽  
Angela Russell ◽  
Angela Hayes ◽  
Florence Raynaud ◽  
...  
Keyword(s):  
Small Molecules ◽  
Protein Interactions ◽  
Binding Sites ◽  
Screening Method ◽  
Chromosomal Translocation ◽  
Resonance Method ◽  
Protein Protein Interactions ◽  
Intracellular Antibody ◽  
A Cell

Intracellular antibodies are tools that can be used directly for target validation by interfering with properties like protein-protein interactions. An alternative use of intracellular antibodies in drug discovery is developing small-molecule surrogates using antibody-derived (Abd) technology. We previously used this strategy with an in vitro competitive surface plasmon resonance method that relied on high-affinity antibody fragments to obtain RAS-binding compounds. We now describe a novel implementation of the Abd method with a cell-based intracellular antibody–guided screening method that we have applied to the chromosomal translocation protein LMO2. We have identified a chemical series of anti-LMO2 Abd compounds that bind at the same LMO2 location as the inhibitory anti-LMO2 intracellular antibody combining site. Intracellular antibodies could therefore be used in cell-based screens to identify chemical surrogates of their binding sites and potentially be applied to any challenging proteins, such as transcription factors that have been considered undruggable.

scholarly journals Prognostic Value and Function of KLF5 in Papillary Thyroid Cancer

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 185
Author(s):  
Poyil Pratheeshkumar ◽  
Abdul K. Siraj ◽  
Sasidharan Padmaja Divya ◽  
Sandeep Kumar Parvathareddy ◽  
Sarah Siraj ◽  
...  
Keyword(s):  
Binding Sites ◽  
Specific Inhibitor ◽  
Papillary Thyroid ◽  
Self Renewal ◽  
Functional Correlation ◽  
Xenograft Growth ◽  
Molecular Therapeutic ◽  
And Function

The Krüppel-like factor 5 (KLF5), a zinc-finger transcriptional factor, is highly expressed in several solid tumors, but its role in PTC remains unclear. We investigated the expression of KLF5 protein in a large cohort of PTC patient samples and explored its functional role and mechanism in PTC cell lines in vitro and in vivo. KLF5 overexpression was observed in 65.1% of all PTC cases and it was significantly associated with aggressive clinico-pathological parameters and poor outcome. Given the significant association between KLF5 and HIF-1α overexpression in PTC patients, we investigated the functional correlation between KLF5 and HIF-1α in PTC cells. Indeed, the analysis revealed the co-immunoprecipitation of KLF5 with HIF-1α in PTC cells. We also identified KLF5-binding sites in the HIF-1α promoter that specifically bound to KLF5 protein. Mechanistically, KLF5 promoted PTC cell growth, invasion, migration, and angiogenesis, while KLF5 downregulation via specific inhibitor or siRNA reverses its action in vitro. Importantly, the silencing of KLF5 decreases the self-renewal ability of spheroids generated from PTC cells. In addition, the depletion of KLF5 reduces PTC xenograft growth in vivo. These findings suggest KLF5 can be a possible new molecular therapeutic target for a subset of PTC.

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