Dataset's files
| Action | DRS | |||
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| HMS_LINCS&file=LDS-1487.tar.gz | Other |
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Project description:The key objectives of this study were to evaluate the selectivity profiles of three MELK inhibitors, 8a, HTH, and OTS, using a cell-based assay, in order to identify a highly selective inhibitor to subsequently investigate MELK function. To this end, we utilized a chemical proteomics approach called multiplexed kinase inhibitor beads/mass spectrometry (MIB/MS) to characterize the selectivity of these MELK inhibitors in TNBC cells.
2020-01-09 | PXD016022 | Pride
Project description:The mechanisms of chronic kidney disease-associated secondary hyperparathyroidism are partially understood. In this project we aimed to gain new information and propose research hypotheses by MS profiling of the PTH mRNA binding proteins and changes upon Pin1 inhibition (which mimics chronic kidney disease).
2022-06-28 | PXD029456 | Pride
Project description:Paracoccidioidomycosis (PCM) is the cause of several deaths from systemic mycoses. The etiological agents of PCM belong to the Paracoccidioides genus, which is restricted to Latin America. The infection is acquired through inhalation of conidia that primarily lodges in the lungs and may disseminate to other organs/tissues. Treatment of PCM is commonly achieved via the administration of antifungals such as amphotericin B, co-trimoxazole, and itraconazole. The antifungal toxicity and side effects, in addition to the long treatment time, have driven research for new bioactive compounds. Argentilactone, a compound isolated from the Brazilian savanna plant Hyptis ovaliofolia, has been suggested to be a potent antifungal, inhibiting the dimorphism of P. brasiliensis and enzymatic activity of isocitrate lyase, a key enzyme of the glyoxylate cycle. Furthermore, argentilactone has no cytotoxicity and genotoxicity in fibroblast cells at concentrations that inhibit fungal growth. This work was developed due to the importance of elucidating the putative mode of action of argentilactone. The chemoproteomics approach, by affinity chromatography, is the methodology used to explore the interactions between P. brasiliensis proteins and argentilactone. A total of 109 proteins was identified and classified functionally, with those related to amino acid metabolism, energy, and detoxification being the most representative. The interactome of argentilactone binding proteins was predicted. Argentilactone inhibited the enzymatic activity of malate dehydrogenase, citrate synthase, and pyruvate dehydrogenase. Furthermore, argentilactone induced the production of reactive oxygen species. In addition, our data were compared to previously obtained proteomics and transcriptional data. Altogether, our results reveal argentilactone as a promising antifungal.
2018-02-07 | PXD008858 | Pride
Project description:Protein kinases are key components in signal transduction pathways and are established drug targets in oncology. Consequently, small molecule kinase inhibitors are on the rise but often show a rather broad target spectrum, potentially leading to toxic side effects. As a result, a broad assessment of the target space is desirable for proper interpretation of observed biological effects. The enzyme Ferrochelatase (FECH), which catalyzes the conversion of protoporphyrin IX into heme, was recently found to be an off-target of the BRAF inhibitor Vemurafenib potentially explaining the often severe phototoxicity associated with this drug in melanoma patients. However, the extent to which kinase inhibitors bind to FECH in general is currently unclear. Here, we used a chemical proteomics approach based on the kinobead technology to profile 226 clinical kinase inhibitors for their potential to bind FECH. Surprisingly, low or sub-micromolar FECH binding was detected for 29 (13%) of all compounds tested and isothermal dose response measurements confirmed drug binding to FECH in cells. We also show that Vemurafenib, Linsitinib, Neratinib and MK-2461 reduce heme levels in K562 cells, verifying that drug binding leads to loss of FECH activity. Further experiments identified the protoporphyrin pocket in FECH as one major binding site for small molecule inhibitors. Since genetic loss of FECH function leads to photosensitivity in humans, we suggest that FECH inhibition by kinase inhibitors is the molecular mechanism triggering photosensitivity in patients and should therefore be part of the pre-clinical tox package for kinase inhibitors.
2017-03-22 | PXD003373 | Pride
Project description:Here, we provide a comprehensive overview of the selectivity profiles of 242 kinase inhibitors currently in clinical trials. We screened available inhibitors against human protein kinases by using the Kinobead technology resulting in a drug matrix identifying the druggable kinome and related proteins.
2017-12-01 | PXD005336 | Pride
Project description:The receptor tyrosine kinase EPHA2 has gained interest as therapeutical drug target in cancer and infectious diseases in the past years. However, EPHA2 research and EPHA2 based therapies have been hampered by the lack of selective small molecule EPHA2 inhibitors. We report on the synthesis and evaluation of dedicated EPHA2 inhibitors based on the clinical BCR-ABL/SRC inhibitor Dasatinib as lead structure. We designed hybrid structures of Dasatinib, CHEBI-513815, PD-173955 and a known EPHB4 inhibitor aiming at the exploitation of the ATP pocket entrance and the ribose pocket. Medicinal chemistry and inhibitor design was guided by a chemical proteomic approach allowing for early selectivity profiling of the newly synthesized inhibitor candidates. Additionally, protein crystallography delivered detailed insight into the molecular interactions that consitute structure-affinity-relationships. Finally, the anti-proliferative effect of the inhibitor candidates was confirmed in the glioblastoma cell line SF-268. In this work, we discovered a novel EPHA2 inhibitor candidate 4a comprising an improved selectivity profile while maintaining potency against EPHA2 and anti-cancer activity in SF-268 cells.
2017-05-30 | PXD006193 | Pride
Project description:Liver receptor homolog-1 (LRH-1) is a phospholipid-sensing nuclear receptor that has shown promise as a target for alleviat-ing intestinal inflammation and disease states characterized by metabolic dysregulation in the liver. LRH-1 contains an unu-sually large ligand binding pocket, and generating synthetic modulators has been challenging. Leveraging a hexahydropen-talene (6HP) core, we have had recent success in generating potent and efficacious agonists through two distinct strategies. We targeted residues deep within the pocket to enhance compound binding, while residues at the mouth of the pocket were targeted to mimic interactions made by endogenous phospholipids. Here, we unite these two designs into one hybrid mole-cule that is the most potent LRH-1 agonist to date. Through a combination of global transcriptomic, biochemical, and struc-tural studies, we show that selective modulation can be driven through contacting deep vs. surface polar regions in the pock-et. While deep pocket contacts convey high-affinity, contacts with the pocket mouth dominate allostery and provide a phos-pholipid-like transcriptional response in cultured cells.
2022-05-04 | PXD031099 | Pride
Project description:The variation among induced pluripotent stem cells (iPSCs) in their differentiation capacity to specific lineages is frequently attributed to somatic memory. In this study, we compared hematopoietic differentiation capacity of 35 human iPSC lines derived from four different tissues and four embryonic stem cell lines. The analysis revealed that hematopoietic commitment capacity (PSCs to hematopoietic precursors) is correlated with the expression level of the IGF2 gene independent of the iPSC origins. In contrast, maturation capacity (hematopoietic precursors to mature blood) is affected by iPSC origin; blood-derived iPSCs showed the highest capacity. However, some fibroblast-derived iPSCs showed higher capacity than blood-derived clones. Tracking of DNA methylation changes during reprogramming reveals that maturation capacity is highly associated with aberrant DNA methylation acquired during reprogramming, rather than the types of iPSC origins. These data demonstrated that variations in the hematopoietic differentiation capacity of iPSCs are not attributable to somatic memories of their origins. Human iPSCs after hematopoietic differentiation (n = 2), human iPSCs after neural differentiation (n = 1), human iPSCs with different culture conditions (n = 8), and human iPSC line forced to express IGF2 gene (n = 1), and its control (n = 1).
2016-06-29 | E-GEOD-75096 | biostudies-arrayexpress
Project description:We investigated the potential role of AMPK in the phosphorylation of ORP8.In vitro kinase assay using purified ORP8 and kinase-active AMPK complex confirmed that ORP8 is the direct substrate of AMPK. Phosphorylated ORP8 from in vitro kinase assay was analyzed by HPLC-MS/MS.
2023-10-24 | PXD036201 | Pride
Project description:Cyclin-Dependent Kinase 9 (CDK9) as part of the PTEFb complex promotes transcriptional elongation by promoting RNAPII pause release. We now report that, paradoxically, CDK9 is also essential for maintaining gene silencing at heterochromatic loci. Through a live cell screen, we discovered that CDK9 inhibition reactivates epigenetically silenced genes in cancer, leading to restored tumor suppressor gene expression and cell differentiation, along with activation of endogenous retrovirus (ERV) genes. CDK9 inhibition dephosphorylates the SWI/SNF protein SMARCA4 and represses HP1α expression, both of which contribute to gene reactivation. Based on gene activation, we developed the highly selective and potent CDK9 inhibitor MC180295 (IC50 =5nM) that has broad anti-cancer activity in-vitro and is effective in in-vivo cancer models. Additionally, CDK9 inhibition sensitizes with the immune checkpoint inhibitor α-PD-1 in vivo, making it an excellent target for epigenetic therapy of cancer.
2020-05-26 | PXD009573 | Pride