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A rationally designed dual PI3-kinase (PI3K) and BET-inhibitory chimeric small molecule demonstrates potent anti-neoplastic activity versus MYC-driven haematological cancers in vivo [scRNA-seq]

ABSTRACT: We hypothesised that PI3K and BET inhibition would synergise in the context of MYC-dysregulation and overcome resistance to single-target inhibition. We then synthesised a series of chimeric molecules linking BET- and PI3K-selective pharmacophores, including our lead molecule, 18D(S). RNA-Seq profiling following acute 18D(S) treatment demonstrated robust transcriptional modulation with concomitant BET and PI3K inhibitory signatures. Our data provides proof-of-concept for the design of potent PI3K- and BET-inhibitors, providing ‘synergy in a single molecule’.

ORGANISM(S): Homo sapiens

PROVIDER: GSE242465 | GEO | 2023/09/07

REPOSITORIES: GEO

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A rationally designed dual PI3-kinase (PI3K) and BET-inhibitory chimeric small molecule demonstrates potent anti-neoplastic activity versus MYC-driven haematological cancers in vivo [ChIP-seq]

Project description:We hypothesised that PI3K and BET inhibition would synergise in the context of MYC-dysregulation and overcome resistance to single-target inhibition. We then synthesised a series of chimeric molecules linking BET- and PI3K-selective pharmacophores, including our lead molecule, 18D(S). RNA-Seq profiling following acute 18D(S) treatment demonstrated robust transcriptional modulation with concomitant BET and PI3K inhibitory signatures. Our data provides proof-of-concept for the design of potent PI3K- and BET-inhibitors, providing ‘synergy in a single molecule’.

2023-08-14 | GSE188442 | GEO

A rationally designed dual PI3-kinase (PI3K) and BET-inhibitory chimeric small molecule demonstrates potent anti-neoplastic activity versus MYC-driven haematological cancers in vivo [RNA-seq]

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A rationally designed dual PI3-kinase (PI3K) and BET-inhibitory chimeric small molecule demonstrates potent anti-neoplastic activity versus MYC-driven haematological cancers in vivo

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-08-14 | GSE188443 | GEO

Therapeutic targeting of GCB- and ABC-DLBCL by rationally designed BCL6 inhibitor

Project description:Rationale: The BCL6 oncogene is constitutively activated by chromosomal translocations and amplification in ABC-DLBCLs, a class of DLBCLs that respond poorly to current therapies. Yet the role of BCL6 in maintaining these lymphomas has not been investigated. BCL6 mediates its effects by recruiting corepressors to an extended groove motif. Development of effective BCL6 inhibitors requires compounds exceeding the binding affinity of these corepressors. Objectives: To design small molecule inhibitors with superior potency vs. endogenous BCL6 ligands for unmet putative therapeutic needs such as targeting ABC-DLBCL. Findings: We used an in silico drug design functional-group mapping approach called SILCS to create a specific BCL6 inhibitor with 10-fold greater potency than endogenous corepressors. The compound, called FX1, binds in such a way as to occupy an essential region of the BCL6 lateral groove. FX1 disrupts BCL6 repression complex formation, reactivates BCL6 target genes, and mimics the phenotype of mice engineered to express BCL6 with lateral groove mutations. This compound eradicated established DLBCLs xenografts at low doses. Most strikingly, FX1 suppressed ABC-DLBCL cells as well as primary human ABC-DLBCL specimens ex vivo. Conclusions: ABC-DLBCL is a BCL6 dependent disease that can be targeted by novel inhibitors able to exceed the binding affinity of natural BCL6 ligands.

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Antibacterial Activity of Rationally Designed Antimicrobial Peptides.

Project description:Many infectious diseases are still prevalent in the world's populations since no effective treatments are available to eradicate them. The reasons may either be the antibiotic resistance towards the available therapeutic molecules or the slow rate of producing adequate therapeutic regimens to tackle the rapid growth of new infectious diseases, as well as the toxicity of current treatment regimens. Due to these reasons, there is a need to seek and develop novel therapeutic regimens to reduce the rapid scale of bacterial infections. Antimicrobial Peptides (AMPs) are components of the first line of defense for prokaryotes and eukaryotes and have a wide range of activities against Gram-negative and Gram-positive bacteria, fungi, cancer cells, and protozoa, as well as viruses. In this study, peptides which were initially identified for their HIV inhibitory activity were further screened for antibacterial activity through determination of their kinetics as well as their cytotoxicity. From the results obtained, the MICs of two AMPs (Molecule 3 and Molecule 7) were 12.5??g/ml for K. pneumoniae (ATCC 700603) and 6.25??g/ml for P. aeruginosa (ATCC 22108). The two AMPs killed these bacteria rapidly in vitro, preventing bacterial growth within few hours of treatment. Furthermore, the cytotoxic activity of these two peptides was significantly low, even at an AMP concentration of 100??g/ml. These results revealed that Molecule 3 and 7 have great potential as antibacterial drugs or could serve as lead compounds in the design of therapeutic regimens for the treatment of antibiotic-resistant bacteria.

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Rationally designed bimetallic Au@Pt nanoparticles for glucose oxidation.

Project description:Bimetallic nanoparticles (NPs) have aroused interest in various fields because of their synergetic and unique properties. Among those nanoparticles, we strategically approached and synthesized Au@Pt NPs via the sonochemical method with different molar ratios (e.g. 3:7, 5:5, and 7:3) of Au to Pt precursors. The particle structure was confirmed to be core-shell, and the size was estimated to be 60, 52, and 47?nm, respectively, for 3:7, 5:5, and 7:3 ratios of Au to Pt. The detailed structure and crystallinity of as-prepared Au@Pt NPs were further studied by scanning electron microscopy, transmission electron microscopy with element mapping, and X-ray diffraction. It should be noted that thickness of the dendritic Pt shell in the core-shell structure can be easily tuned by controlling the molar ratio of Au to Pt. To explore the possibility of this material as glucose sensor, we confirmed the detection of glucose using amperometry. Two dynamic ranges in a calibration plot were displayed at 0.5-50.0?µM and 0.05-10.0?mM, and their detection limit as glucose sensor was determined to be 319.8 (±5.4) nM.

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Project description:Seeding, in the context of amyloid disease, is the sequential transfer of pathogenic protein aggregates from cell-to-cell within affected tissues. The structure of pathogenic seeds provides the molecular basis and enables rapid conversion of soluble protein into fibrils. To date, there are no inhibitors that specifically target seeding of Parkinson's disease (PD)-associated α-synuclein (α-syn) fibrils, in part, due to lack of information of the structural properties of pathological seeds. Here we design small peptidic inhibitors based on the atomic structure of the core of α-syn fibrils. The inhibitors prevent α-syn aggregation in vitro and in cell culture models with binding affinities of 0.5 μM to α-syn fibril seeds. The inhibitors also show efficacy in preventing seeding by human patient-derived α-syn fibrils. Our results suggest that pathogenic seeds of α-syn contain steric zippers and suggest a therapeutic approach targeted at the spread and progression that may be applicable for PD and related synucleinopathies.

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Dual kinase-bromodomain inhibitors for rationally designed polypharmacology.

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2018-08-05 | GSE110858 | GEO

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