RNA-Seq to Explore 2-Sulfonylpyrimidine Warheads as Acrylamide Surrogates for Targeted Covalent Inhibition of BTK in Diffuse Large B Cell (DLBCL) Cell Line TMD8
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB79016 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR13499000_1.fastq.gz | Fastqsanger.gz | |||
| ERR13499000_2.fastq.gz | Fastqsanger.gz | |||
| ERR13499001_1.fastq.gz | Fastqsanger.gz | |||
| ERR13499001_2.fastq.gz | Fastqsanger.gz | |||
| ERR13499002_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 36 |
Similar Datasets
Project description:Bruton Tyrosine Kinase (BTK) plays an essential role in signal transduction downstream of cell surface receptors on B lymphocytes, including the B-cell receptor (BCR), a key driver of several sub-types of human B-cell lymphoma and leukaemia. As such, BTK inhibitors have proven to be effective therapies for B-cell malignancies, most notably Ibrutinib. Targeted covalent inhibitors (TCIs) directing cysteine typically rely on a narrow set of electrophilic “warheads”. Michael acceptors remain at the forefront of TCI design strategies, yet have variable stability and selectivity under physiological conditions. Our RNA-Seq experiments were performed on TMD8 cells that had been cultured for 8 hours with DMSO, ibrutinib or 4 chemical constructs that we describe in Moraru et al. (2024), resulting in a total of 18 libraries. Our data show that the 2-sulfonylpyrimidine motif is an effective replacement for the acrylamide warhead of Ibrutinib.
2024-08-29 | E-MTAB-14363 | biostudies-arrayexpress
Project description:To investagate the clinically observed BTK C481S, C481F, C481Y and C481R mutations in the regulation of B cell receptor signaling, we extablished TMD8 cells expressing BTK C481S, C481F, C481Y and C481R in which endogenous BTK was inactivated by ibrutinib. We then performed gene expression profiling analysis using data obtained from RNA-seq of 20 different cells after DMSO or 10 nM ibrutinib treatment from two indenpendent experiments.
2022-11-29 | GSE207322 | GEO
Project description:Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are the most prevalent B-lymphocyte neoplasms in which abnormal activation of the Bruton’s tyrosine kinase (BTK)–mediated B-cell receptor (BCR) signaling pathway contributes to pathogenesis. Ibrutinib is an oral covalent BTK inhibitor that has shown some efficacy in both indications. To improve ibrutinib efficacy through combination therapy, we first investigated differential gene expression in parental and ibrutinib-resistant cell lines to better understand the mechanisms of resistance. Ibrutinib-resistant TMD8 cells had higher BCL2 gene expression and increased sensitivity to ABT-199, a BCL-2 inhibitor. Consistently, clinical samples from ABC-DLBCL patients who experienced poorer response to ibrutinib had higher BCL2 gene expression. We further demonstrated synergistic growth suppression by ibrutinib and ABT-199 in multiple ABC-DLBCL, GCB-DLBCL, and FL lymphoma cell lines. The combination of both drugs also reduced colony formation, increased apoptosis, and inhibited tumor growth in a TMD8 xenograft model. A synergistic combination effect was also found in ibrutinib-resistant cells generated by either genetic mutation or drug treatment. Together, these findings suggest a potential clinical benefit from ibrutinib and ABT-199 combination therapy.
2017-04-30 | GSE93985 | GEO
Project description:Targeted covalent inhibitors (TCIs) directing cysteine have historically relied on a narrow set of electrophilic "warheads". While Michael acceptors remain at the forefront of TCI design strategies, they show variable stability and selectivity under physiological conditions. Here, we show that the 2-sulfonylpyrimidine motif is an effective replacement for the acrylamide warhead of Ibrutinib, for the inhibition of Bruton's tyrosine kinase. In a few iterations, we discovered new derivatives, which inhibit BTK both in vitro and in cellulo at low nanomolar concentrations, on par with Ibrutinib. Several derivatives also displayed good plasma stability and reduced off-target binding in vitro across 135 tyrosine kinases. This proof-of-concept study on a well-studied kinase/TCI system highlights the 2-sulfonylpyrimidine group as a useful acrylamide replacement. In the future, it will be interesting to investigate its wider potential for developing TCIs with improved pharmacologies and selectivity profiles across structurally related protein families.
| S-EPMC11345841 | biostudies-literature
Project description:The goal of this study is to examine gene expression changes in TMD8 KLHL14(+/+) or TMD8 KLHL14(-/-) cells during ibrutinib treatment. The samples have 35 to 63 million pass filter reads with more than 92% of bases above the quality score of Q30.The average mapping rate of all samples is 95%. Unique alignment is above 86%. There are 3.65 to 6.25% unmapped reads.The mapping statistics are calculated using Picard software. The samples have between 0.86-1.29% ribosomal bases. Percent coding bases are between 58-62%. Percent UTR bases are 27-31%, and mRNA bases are between 87-90% for all the samples. We show that TMD8 KLHL14(-/-) cells have less down-regulation of NF-kB signatures and IL10/JAK1/STAT3 signatures upon ibrutinib treatment when compared to TMD8 KLHL14(+/+) cells.
2020-03-03 | GSE141143 | GEO
Project description:Current efforts in the proteolysis targeting chimera (PROTAC) field mostly focus on choosing the appropriate E3 ligase for a certain targeted protein, improving the binding affinities towards the target protein and the E3 ligase, and optimizing the PROTAC linker. However, it is well known that due to the large sizes of PROTAC molecules, their cellular uptake level remains an issue, posing a challenge to translate PROTACs into therapeutics. Driven by our fundamental investigation to compare how different warhead chemistry, reversible noncovalent (RNC), reversible covalent (RC), and irreversible covalent (IRC) binders, may affect the degradation of a model protein Bruton's Tyrosine Kinase (BTK), we serendipitously discovered that cyano-acrylamide-based reversible covalent chemistry can significantly enhance the intracellular concentration and target engagement of the PROTAC. Building on this discovery, we developed RC-1 as the first reversible covalent BTK PROTAC, which has high target occupancy and is effective as both an inhibitor and a degrader. Molecular dynamics calculations and phase-separation based ternary complex assays support that RC-1 forms a stable ternary complex with BTK and Cereblon (CRBN). Additionally, RC-1 compares favorably with other reported BTK degraders in cell viability and target engagement assays and has a reasonable plasma half-life for in vivo applications. Importantly, this reversible covalent strategy can be generalized and applied to improve other PROTACs. This work can not only help to develop optimal BTK degraders for clinical applications but also provide a new strategy to improve PROTAC efficacy.
2020-02-04 | MSV000084902 | MassIVE
Project description:Multi-omics exploration of microenvironmental changes during BTK covalent inhibition in chronic lymphocytic leukemia
| PRJNA1071569 | ENA
Project description:Acrylamide is a type-2 alkene monomer with established human neurotoxic effects. While the primary source of human exposure to acrylamide is occupational, other exposure sources include food, drinking water, and smoking. In this study, neurobehavioral assays coupled with transcriptional profiling analysis were conducted to assess both behavioral and gene expression effects induced by acrylamide neurotoxicity in rats when administered during early postnatal life. Acrylamide administration in rat pups induced significant characteristic neurotoxic symptoms including increased heel splay, decrease in grip strength, and decrease in locomotor activity. Transcriptome analysis with the Affymetrix Rat Genome 230 2.0 array indicated that acrylamide treatment caused a significant alteration in the expression of genes involved in muscle contraction, pain regulation, and dopaminergic neuronal pathways. First, in agreement with the observed behavioral effects, expression of the Mylpf gene involved in muscle contraction was downregulated in the spinal cord in response to acrylamide. Second, in sciatic nerves, acrylamide repressed the expression of the opioid receptor gene Oprk1 that is known to play a role in neuropathic pain regulation. Finally, in the cerebellum, acrylamide treatment caused a decrease in the expression of the nuclear receptor gene Nr4a2 that is required for development of dopaminergic neurons. Thus, our work examining the effect of acrylamide at the whole-genome level on a developmental mammalian model has identified novel genes previously not implicated in acrylamide neurotoxicity that can be further developed into biomarkers for assessing the risk of acrylamide exposure.
2012-02-08 | GSE29004 | GEO
Project description:Acrylamide, a high-production-volume chemical and food contaminant in baked and fried carbohydrate-rich foods has been classified as a “Group 2A carcinogen” (probable human carcinogen) by the IARC. The carcinogenicity of acrylamide is attributed to its well-recognized genotoxicity; however, evidence suggests that acrylamide may also induce non-genotoxic alterations. In the present study female B6C3F1 mice were exposed to 0.70mM acrylamide in drinking water for 28 days and genotoxic and transcriptomic effects were investigated in the lung, a target organ for acrylamide carcinogenicity in mice, and the liver, a non-target organ. Acrylamide exposure resulted in a dose-dependent formation of N7-(2-carbamoyl-2-hydroxyethyl)guanine and N3-(2-carbamoyl-2-hydroxyethyl)adenine in lung and liver DNA at the similar levels. In contrast, whole genome gene expression profiles in the lungs and livers revealed the tissue-specific gene expression alterations. By using a SurePrint G3 Mouse Gene Expression v2 8x60K Microarray Kit (Agilent Technologies), we identified 123 and 363 genes that were found to be differentially expressed in the lungs and livers of acrylamide-treated mice; however, only 5 genes were in common between the organs. A detailed analysis of differentially expressed genes revealed that the major difference in the effect of acrylamide on the transcriptome in the lungs and livers was related to a different trend of gene expression changes. In the lungs, acrylamide exposure caused an inhibition of gene expression (54 up-regulated and 69 down-regulated genes), whereas the opposite effect, characterized by twice the number of up-regulated as compare to down-regulated genes (245 up-regulated and 118 down-regulated), was found in the livers of exposed mice.
2019-01-30 | GSE125851 | GEO
Project description:Effect of clinically observed BTK mutations on gene expression during cell proliferation and differentiation in TMD8 cells
| PRJNA854807 | ENA