A chemical biology approach reveals a dependency of glioblastoma on biotin distribution.
Ontology highlight
ABSTRACT:
SUBMITTER: Yoon J
PROVIDER: S-EPMC8442857 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Continuous flow (microfluidic) chemistry was employed to prepare a small focused library of dihydropyrimidinone (DHPM) derivatives. Compounds in this class have been reported to exhibit activity against the human immunodeficiency virus (HIV), but their molecular target had not been identified. We tested the initial set of DHPMs in phenotypic assays providing a hit (1i) that inhibited the replication of the human immunodeficiency virus HIV in cells. Flow chemistry-driven optimization of 1i led to the identification of HIV replication inhibitors such as 1l with cellular potency comparable with the clinical drug nevirapine (NVP). Mechanism of action (MOA) studies using cellular and biochemical assays coupled with 3D fingerprinting and in silico modeling demonstrated that these drug-like probe compounds exert their effects by inhibiting the viral reverse transcriptase polymerase (RT). This led to the design and synthesis of the novel DHPM 1at that inhibits the replication of drug resistant strains of HIV. Our work demonstrates that combining flow chemistry-driven analogue refinement with phenotypic assays, in silico modeling and MOA studies is a highly effective strategy for hit-to-lead optimization applicable to the discovery of future therapeutic agents.
| S-EPMC6145176 | biostudies-literature
Project description:Glucocorticoids display remarkable anti-inflammatory activity, but their use is limited by on-target adverse effects including insulin resistance and skeletal muscle atrophy. We used a chemical systems biology approach, ligand class analysis, to examine ligands designed to modulate glucocorticoid receptor activity through distinct structural mechanisms. These ligands displayed diverse activity profiles, providing the variance required to identify target genes and coregulator interactions that were highly predictive of their effects on myocyte glucose disposal and protein balance. Their anti-inflammatory effects were linked to glucose disposal but not muscle atrophy. This approach also predicted selective modulation in vivo, identifying compounds that were muscle-sparing or anabolic for protein balance and mitochondrial potential. Ligand class analysis defined the mechanistic links between the ligand-receptor interface and ligand-driven physiological outcomes, a general approach that can be applied to any ligand-regulated allosteric signaling system.
| S-EPMC8783757 | biostudies-literature
Project description:The circadian clock controls daily oscillations of gene expression at the cellular level. We report the development of a high-throughput circadian functional assay system that consists of luminescent reporter cells, screening automation, and a data analysis pipeline. We applied this system to further dissect the molecular mechanisms underlying the mammalian circadian clock using a chemical biology approach. We analyzed the effect of 1,280 pharmacologically active compounds with diverse structures on the circadian period length that is indicative of the core clock mechanism. Our screening paradigm identified many compounds previously known to change the circadian period or phase, demonstrating the validity of the assay system. Furthermore, we found that small molecule inhibitors of glycogen synthase kinase 3 (GSK-3) consistently caused a strong short period phenotype in contrast to the well-known period lengthening by lithium, another presumed GSK-3 inhibitor. siRNA-mediated knockdown of GSK-3beta also caused a short period, confirming the phenotype obtained with the small molecule inhibitors. These results clarify the role of GSK-3beta in the period regulation of the mammalian clockworks and highlight the effectiveness of chemical biology in exploring unidentified mechanisms of the circadian clock.
| S-EPMC2606900 | biostudies-literature
Project description:Plants have a large family of membrane receptor kinases (RKs) which sense extracellular signals to control plant growth, development, immunity, and stress response. The largest group of RKs contains an extracellular leucine-rich repeat (LRR) domain with over 200 members in Arabidopsis. However, the functional understanding of most of the LRR-RKs has been hampered by their genetic redundancy and the subtle phenotypes of RK overexpression. Here we show that the rapamycin-mediated heterodimerization of chimeric cytosolic kinase domains from receptor/co-receptor pairs in the plasma membrane can activate their downstream cellular signaling pathway, inducing the specific biological responses, including brassinosteroid, plant immunity, stomatal development, and lateral root development. This chemically controlled synthetic biology approach will be useful to investigate biological functions of LRR-RKs and their signaling pathways.
2021-06-10 | GSE136177 | GEO
Project description:Compound screening in biological assays and subsequent optimization of hits is indispensable for the development of new molecular research tools and drug candidates. To facilitate such discoveries, the European Research Infrastructure EU-OPENSCREEN was founded recently with the support of its member countries and the European Commission. Its distributed character harnesses complementary knowledge, expertise, and instrumentation in the discipline of chemical biology from 20 European partners, and its open working model ensures that academia and industry can readily access EU-OPENSCREEN's compound collection, equipment, and generated data. To demonstrate the power of this collaborative approach, this perspective article highlights recent projects from EU-OPENSCREEN partner institutions. These studies yielded (1) 2-aminoquinazolin-4(3 H)-ones as potential lead structures for new antimalarial drugs, (2) a novel lipodepsipeptide specifically inducing apoptosis in cells deficient for the pVHL tumor suppressor, (3) small-molecule-based ROCK inhibitors that induce definitive endoderm formation and can potentially be used for regenerative medicine, (4) potential pharmacological chaperones for inborn errors of metabolism and a familiar form of acute myeloid leukemia (AML), and (5) novel tankyrase inhibitors that entered a lead-to-candidate program. Collectively, these findings highlight the benefits of small-molecule screening, the plethora of assay designs, and the close connection between screening and medicinal chemistry within EU-OPENSCREEN.
| S-EPMC6764006 | biostudies-literature
Project description:Glucocorticoids display remarkable anti-inflammatory activity, but their use is limited by undesirable on-target effects including insulin resistance and skeletal muscle atrophy. We used a chemical systems biology approach called Ligand Class Analysis (LCA) to examine ligands designed to alter the receptor through distinct structural mechanisms. These ligands displayed a full range of activity profiles, providing the variance required to identify ligand-specific gene expression and transcriptional coregulator interaction patterns that were highly predictive of their effects on myocyte glucose disposal and protein balance. Anti-inflammatory effects were linked to inhibition of glucose disposal in skeletal muscle but not to muscle atrophy. This approach successfully predicted dissociated activity in vivo, identifying compounds that were muscle sparing or anabolic for protein balance and mitochondrial potential. LCA defines the mechanistic links between the ligand-receptor interface and the physiological outcomes of the ligands, a general approach that can be applied to any ligand-regulated allosteric signaling system.
2020-09-08 | GSE149453 | GEO
Project description:Using small molecule probes to understand gene function is an attractive approach that allows functional characterization of genes that are dispensable in standard laboratory conditions and provides insight into the mode of action of these compounds. Using chemogenomic assays we previously identified yeast Crg1, an uncharacterized SAM-dependent methyltransferase, as a novel interactor of the protein phosphatase inhibitor cantharidin. In this study we used a combinatorial approach that exploits contemporary high-throughput techniques available in Saccharomyces cerevisiae combined with rigorous biological follow-up to characterize the interaction of Crg1 with cantharidin. Biochemical analysis of this enzyme followed by a systematic analysis of the interactome and lipidome of CRG1 mutants revealed that Crg1, a stress-responsive SAM-dependent methyltransferase, methylates cantharidin in vitro. Chemogenomic assays uncovered that lipid-related processes are essential for cantharidin resistance in cells sensitized by deletion of the CRG1 gene. Lipidome-wide analysis of mutants further showed that cantharidin induces alterations in glycerophospholipid and sphingolipid abundance in a Crg1-dependent manner. We propose that Crg1 is a small molecule methyltransferase important for maintaining lipid homeostasis in response to drug perturbation. This approach demonstrates the value of combining chemical genomics with other systems-based methods for characterizing proteins and elucidating previously unknown mechanisms of action of small molecule inhibitors.
| S-EPMC3197675 | biostudies-literature
Project description:Doublecortin-like kinase 1 (DCLK1) is critical for neurogenesis, but overexpression is also observed in multiple cancers and is associated with poor prognosis. Nevertheless, the function of DCLK1 in cancer, especially the context-dependent functions, are poorly understood. We present a "toolkit" that includes the DCLK1 inhibitor DCLK1-IN-1, a complementary DCLK1-IN-1-resistant mutation G532A, and kinase dead mutants D511N and D533N, which can be used to investigate signaling pathways regulated by DCLK1. Using a cancer cell line engineered to be DCLK1 dependent for growth and cell migration, we show that this toolkit can be used to discover associations between DCLK1 kinase activity and biological processes. In particular, we show an association between DCLK1 and RNA processing, including the identification of CDK11 as a potential substrate of DCLK1 using phosphoproteomics.
| S-EPMC8053042 | biostudies-literature
Project description:Guggulsterone is a promiscuous ligand for endocrine and metabolic lipid receptors traditionally used to treat a number of diseases including diabesity, hyperlipidemia, atherosclerosis, and osteoarthritis. Although relatively weak, its activity at the farnesoid X receptor (FXR) is particularly intriguing as guggulsterone acts as an antagonist with a peculiar ability of gene selective modulation. We report here a chemical biology study with the aim to further characterize the biological action of guggulsterone at the FXR and to obtain further insights into the functional role played by noncanonical FXR binding pockets S2 and S3. Our results suggest that the FXR accessory pockets might act as potential targets for small molecules able to modulate the metabolic activation of the receptor without affecting the anti-inflammatory activity thus revealing a new approach for disclosing selective FXR modulators that might bypass potential side-effects from chronic treatments.
| S-EPMC6786047 | biostudies-literature
Project description:The understanding of how aging contributes to dementia remains obscure. To address this problem, a chemical biology approach was used employing CAD031, an Alzheimer's disease (AD) drug candidate identified using a discovery platform based upon phenotypic screens that mimic toxicities associated with the aging brain. Since CAD031 has therapeutic efficacy when fed to old symptomatic transgenic AD mice, the chemical biology hypothesis is that it can be used to determine the molecular pathways associated with age-related disease by identifying those that are modified by the compound. Here we show that when CAD031 was fed to rapidly aging SAMP8 mice starting in the last quadrant of their lifespan, it reduced many of the changes in gene, protein, and small molecule expression associated with mitochondrial aging, maintaining mitochondria at the younger molecular phenotype. Network analysis integrating the metabolomics and transcription data followed by mechanistic validation showed that CAD031 targets acetyl-CoA and fatty acid metabolism via the AMPK/ACC1 pathway. Importantly, CAD031 extended the median lifespan of SAMP8 mice by about 30%. These data show that specific alterations in mitochondrial composition and metabolism highly correlate with aging, supporting the use AD drug candidates that limit physiological aging in the brain.
| S-EPMC8050149 | biostudies-literature