当前位置： SCI文献检索 > ACS Chemical Biology期刊下所有文献 > Small Molecule Phenotypic Screen Identifies Novel Regulators of LDLR Expression.

Small Molecule Phenotypic Screen Identifies Novel Regulators of LDLR Expression.

Abstract：

:Alzheimer's Disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia. The current treatment options for AD are limited to ameliorating cognitive decline temporarily and not reversing or preventing the progression of dementia. Hence, more effective therapeutic strategies are needed to combat this devastating disease. The low-density lipoprotein receptor has been shown to modulate the neuronal metabolism of cholesterol and apolipoprotein E, a major genetic risk factor for AD. LDLR overexpression in mice has been shown to increase amyloid-β clearance and reduce amyloid deposition. We conducted a phenotypic screen to identify novel signaling pathways and targets that regulate LDLR expression in glial cells using an annotated compound library of approximately 29 000 compounds. The screen identified novel targets such as polo like kinase 1 (PLK1), activin receptor like kinase 5 (ALK5), and serotonin transporter (SERT). We used genetic, chemical biology and pathway analysis to confirm the target hypothesis. This work highlights that phenotypic screening is a promising strategy to identify novel mechanisms and targets for therapeutic intervention of complex neurodegenerative disorders.

journal_name

ACS Chem Biol

journal_title

ACS chemical biology

authors

Krishnan N,Chen X,Donnelly-Roberts D,Mohler EG,Holtzman DM,Gopalakrishnan SM

doi

10.1021/acschembio.0c00851

subject

Has Abstract

pub_date

2020-12-18 00:00:00

pages

3262-3274

issue

12

eissn

1554-8929

issn

1554-8937

journal_volume

15

pub_type

杂志文章

相关文献

ACS Chemical Biology文献大全
  • Efficient NQO1 substrates are potent and selective anticancer agents.

    abstract：:A major goal of personalized medicine in oncology is the identification of drugs with predictable efficacy based on a specific trait of the cancer cell, as has been demonstrated with gleevec (presence of Bcr-Abl protein), herceptin (Her2 overexpression), and iressa (presence of a specific EGFR mutation). This is a cha...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb4005832

    authors： Parkinson EI,Bair JS,Cismesia M,Hergenrother PJ

    更新日期：2013-10-18 00:00:00

  • A whole more than the sum of its synthetic parts.

    abstract：:Synthetic biology is the realization of systems with desired behavior using biological materials. A recent addition to the field is a bipartite consortium of the bacterium Escherichia coli in which each species harbors complementary gene circuits that actuate only when both are present above a critical density. This b...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb700256w

    authors： Wong JV,Song H,You L

    更新日期：2008-01-18 00:00:00

  • Reporter enzyme inhibitor study to aid assembly of orthogonal reporter gene assays.

    abstract：:Reporter gene assays (RGAs) are commonly used to measure biological pathway modulation by small molecules. Understanding how such compounds interact with the reporter enzyme is critical to accurately interpret RGA results. To improve our understanding of reporter enzymes and to develop optimal RGA systems, we investig...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb3007264

    authors： Ho PI,Yue K,Pandey P,Breault L,Harbinski F,McBride AJ,Webb B,Narahari J,Karassina N,Wood KV,Hill A,Auld DS

    更新日期：2013-05-17 00:00:00

  • Role of pseudouridine in structural rearrangements of helix 69 during bacterial ribosome assembly.

    abstract：:As part of the central core domain of the ribosome, helix 69 of 23S rRNA participates in an important intersubunit bridge and contacts several protein translation factors. Helix 69 is believed to play key roles in protein synthesis. Even though high-resolution crystal structures of the ribosome exist, the solution dyn...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb200497q

    authors： Sakakibara Y,Chow CS

    更新日期：2012-05-18 00:00:00

  • Targeting conformational plasticity of protein kinases.

    abstract：:The quest for ever more selective kinase inhibitors as potential future drugs has yielded a large repertoire of chemical probes that are selective for specific kinase conformations. These probes have been useful tools to obtain structural snapshots of kinase conformational plasticity. Similarly, kinetic and thermodyna...

    journal_title：ACS chemical biology

    pub_type： 杂志文章,评审

    doi：10.1021/cb500870a

    authors： Tong M,Seeliger MA

    更新日期：2015-01-16 00:00:00

  • Studying weak and dynamic interactions of posttranslationally modified proteins using expressed protein ligation.

    abstract：:Many cellular processes are regulated by posttranslational modifications that are recognized by specific domains in protein binding partners. These interactions are often weak, thus allowing a highly dynamic and combinatorial regulatory network of protein-protein interactions. We report an efficient strategy that over...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb400723j

    authors： Tripsianes K,Chu NK,Friberg A,Sattler M,Becker CF

    更新日期：2014-02-21 00:00:00

  • Structure-based design of an organoruthenium phosphatidyl-inositol-3-kinase inhibitor reveals a switch governing lipid kinase potency and selectivity.

    abstract：:Mutations that constitutively activate the phosphatidyl-inositol-3-kinase (PI3K) signaling pathway, including alterations in PI3K, PTEN, and AKT, are found in a variety of human cancers, implicating the PI3K lipid kinase as an attractive target for the development of therapeutic agents to treat cancer and other relate...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb800039y

    authors： Xie P,Williams DS,Atilla-Gokcumen GE,Milk L,Xiao M,Smalley KS,Herlyn M,Meggers E,Marmorstein R

    更新日期：2008-05-16 00:00:00

  • Quantitative Chemical Proteomic Profiling of Ubiquitin Specific Proteases in Intact Cancer Cells.

    abstract：:Deubiquitinating enzymes play an important role in a plethora of therapeutically relevant processes and are emerging as pioneering drug targets. Herein, we present a novel probe, Ubiquitin Specific Protease (USP) inhibitor, alongside an alkyne-tagged activity-based probe analogue. Activity-based proteome profiling ide...

    journal_title：ACS chemical biology

    pub_type： 信件

    doi：10.1021/acschembio.6b00766

    authors： Ward JA,McLellan L,Stockley M,Gibson KR,Whitlock GA,Knights C,Harrigan JA,Jacq X,Tate EW

    更新日期：2016-12-16 00:00:00

  • Transferrin Cycle and Clinical Roles of Citrate and Ascorbate in Improved Iron Metabolism.

    abstract：:Fe(III) delivery from blood plasma to cells via the transferrin (Tf) cycle was studied intensively due to its crucial role in Fe homeostasis. Tf-cycle disruptions are linked to anemia, infections, immunodeficiency, and neurodegeneration. Biolayer interferometry (BLI) enabled direct kinetic and thermodynamic measuremen...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/acschembio.8b01100

    authors： Levina A,Lay PA

    更新日期：2019-05-17 00:00:00

  • Antagonism of c-IAP and XIAP proteins is required for efficient induction of cell death by small-molecule IAP antagonists.

    abstract：:The inhibitor of apoptosis (IAP) proteins are critical regulators of cancer cell survival, which makes them attractive targets for therapeutic intervention in cancers. Herein, we describe the structure-based design of IAP antagonists with high affinities and selectivity (>2000-fold) for c-IAP1 over XIAP and their func...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb900083m

    authors： Ndubaku C,Varfolomeev E,Wang L,Zobel K,Lau K,Elliott LO,Maurer B,Fedorova AV,Dynek JN,Koehler M,Hymowitz SG,Tsui V,Deshayes K,Fairbrother WJ,Flygare JA,Vucic D

    更新日期：2009-07-17 00:00:00

  • Competitive binding of a benzimidazole to the histone-binding pocket of the Pygo PHD finger.

    abstract：:The Pygo-BCL9 complex is a chromatin reader, facilitating β-catenin-mediated oncogenesis, and is thus emerging as a potential therapeutic target for cancer. Its function relies on two ligand-binding surfaces of Pygo's PHD finger that anchor the histone H3 tail methylated at lysine 4 (H3K4me) with assistance from the B...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb500585s

    authors： Miller TC,Rutherford TJ,Birchall K,Chugh J,Fiedler M,Bienz M

    更新日期：2014-12-19 00:00:00

  • Functional and Structural Insights into a Novel Promiscuous Ketoreductase of the Lugdunomycin Biosynthetic Pathway.

    abstract：:Angucyclines are a structurally diverse class of actinobacterial natural products defined by their varied polycyclic ring systems, which display a wide range of biological activities. We recently discovered lugdunomycin (1), a highly rearranged polyketide antibiotic derived from the angucycline backbone that is synthe...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/acschembio.0c00564

    authors： Xiao X,Elsayed SS,Wu C,van der Heul HU,Metsä-Ketelä M,Du C,Prota AE,Chen CC,Liu W,Guo RT,Abrahams JP,van Wezel GP

    更新日期：2020-09-18 00:00:00

  • Conformational Changes in Alkyl Chains Determine the Thermodynamic and Kinetic Binding Profiles of Carbonic Anhydrase Inhibitors.

    abstract：:Thermodynamics and kinetics of protein-ligand binding are both important aspects for the design of novel drug molecules. Presently, thermodynamic data are collected with isothermal titration calorimetry, while kinetic data are mostly derived from surface plasmon resonance. The new method of kinITC provides both thermo...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/acschembio.9b00895

    authors： Glöckner S,Ngo K,Sager CP,Hüfner-Wulsdorf T,Heine A,Klebe G

    更新日期：2020-03-20 00:00:00

  • Structural and Biosynthetic Analysis of the Fabrubactins, Unusual Siderophores from Agrobacterium fabrum Strain C58.

    abstract：:Siderophores are iron-chelating molecules produced by microorganisms and plants to acquire exogenous iron. Siderophore biosynthetic enzymology often produces elaborate and unique molecules through unusual reactions to enable specific recognition by the producing organisms. Herein, we report the structure of two sidero...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/acschembio.0c00809

    authors： Vinnik V,Zhang F,Park H,Cook TB,Throckmorton K,Pfleger BF,Bugni TS,Thomas MG

    更新日期：2021-01-15 00:00:00

  • Multiple Chemical Inducible Tal Effectors for Genome Editing and Transcription Activation.

    abstract：:Inducible modulation is often required for precise investigations and manipulations of dynamic biological processes. Transcription activator-like effectors (TALEs) provide a powerful tool for targeted gene editing and transcriptional programming. We designed a series of chemical inducible systems by coupling TALEs wit...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/acschembio.7b00606

    authors： Zhao C,Zhang Y,Zhao Y,Ying Y,Ai R,Zhang J,Wang Y

    更新日期：2018-03-16 00:00:00

  • Discovery and Characterization of a Potent and Specific Peptide Ligand Targeting Endothelial Progenitor Cells and Endothelial Cells for Tissue Regeneration.

    abstract：:Endothelial progenitor cells (EPCs) and endothelial cells (ECs) play a vital role in endothelialization and vascularization for tissue regeneration. Various EPC/EC targeting biomolecules have been investigated to improve tissue regeneration with limited success often due to their limited functional specificity and str...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/acschembio.7b00118

    authors： Hao D,Xiao W,Liu R,Kumar P,Li Y,Zhou P,Guo F,Farmer DL,Lam KS,Wang F,Wang A

    更新日期：2017-04-21 00:00:00

  • Stabilization of physical RAF/14-3-3 interaction by cotylenin A as treatment strategy for RAS mutant cancers.

    abstract：:One-third of all human cancers harbor somatic RAS mutations. This leads to aberrant activation of downstream signaling pathways involving the RAF kinases. Current ATP-competitive RAF inhibitors are active in cancers with somatic RAF mutations, such as BRAF(V600) mutant melanomas. However, they paradoxically promote th...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb4003464

    authors： Molzan M,Kasper S,Röglin L,Skwarczynska M,Sassa T,Inoue T,Breitenbuecher F,Ohkanda J,Kato N,Schuler M,Ottmann C

    更新日期：2013-09-20 00:00:00

  • Systematic Synthesis and Binding Study of HIV V3 Glycopeptides Reveal the Fine Epitopes of Several Broadly Neutralizing Antibodies.

    abstract：:A class of new glycan-reactive broadly neutralizing antibodies represented by PGT121, 10-1074, and PGT128 has recently been discovered that targets specific N-glycans and the peptide region around the V3 domain. However, the glycan specificity and fine epitopes of these bNAbs remain to be further defined. We report he...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/acschembio.7b00319

    authors： Orwenyo J,Cai H,Giddens J,Amin MN,Toonstra C,Wang LX

    更新日期：2017-06-16 00:00:00

  • A new approach for enhancing differential selectivity of drugs to cancer cells.

    abstract：:The degree to which anticancer agents selectively target cancer cells is a key determinant in successful therapeutic outcomes. Inhibitors of the Hsp90 molecular chaperone represent an important new class of anticancer agents. We propose here a novel mechanism by which physiochemical properties of Hsp90 inhibitors can ...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb6001202

    authors： Duvvuri M,Konkar S,Hong KH,Blagg BS,Krise JP

    更新日期：2006-06-20 00:00:00

  • Identification of small molecule modulators of gene transcription with anticancer activity.

    abstract：:Epigenetic regulation of gene expression is essential in many biological processes, and its deregulation contributes to pathology including tumor formation. We used an image-based cell assay that measures the induction of a silenced GFP-estrogen receptor reporter to identify novel classes of small molecules involved i...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb500532x

    authors： Tran TA,Wichterman-Kouznetsova J,Varghese D,Huang R,Huang W,Becker M,Austin CP,Inglese J,Johnson RL,Martinez ED

    更新日期：2014-11-21 00:00:00

  • Adversarial Controls for Scientific Machine Learning.

    abstract：:New machine learning methods to analyze raw chemical and biological data are now widely accessible as open-source toolkits. This positions researchers to leverage powerful, predictive models in their own domains. We caution, however, that the application of machine learning to experimental research merits careful cons...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/acschembio.8b00881

    authors： Chuang KV,Keiser MJ

    更新日期：2018-10-19 00:00:00

  • Cell-penetrating bisubstrate-based protein kinase C inhibitors.

    abstract：:Although protein kinase inhibitors present excellent pharmaceutical opportunities, lack of selectivity and associated therapeutic side effects are common. Bisubstrate-based inhibitors targeting both the high-selectivity peptide substrate binding groove and the high-affinity ATP pocket address this. However, they are t...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb300709g

    authors： van Wandelen LT,van Ameijde J,Ismail-Ali AF,van Ufford HC,Vijftigschild LA,Beekman JM,Martin NI,Ruijtenbeek R,Liskamp RM

    更新日期：2013-07-19 00:00:00

  • The STAT5b Linker Domain Mediates the Selectivity of Catechol Bisphosphates for STAT5b over STAT5a.

    abstract：:STAT family proteins are important mediators of cell signaling and represent therapeutic targets for the treatment of human diseases. Most STAT inhibitors target the protein-protein interaction domain, the SH2 domain, but specificity for a single STAT protein is often limited. Recently, we developed catechol bisphosph...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/acschembio.9b00137

    authors： Gräb J,Berg A,Blechschmidt L,Klüver B,Rubner S,Fu DY,Meiler J,Gräber M,Berg T

    更新日期：2019-04-19 00:00:00

  • Small molecule inhibitors of bromodomain-acetyl-lysine interactions.

    abstract：:Bromodomains are protein modules that bind to acetylated lysine residues. Their interaction with histone proteins suggests that they function as "readers" of histone lysine acetylation, a component of the proposed "histone code". Bromodomain-containing proteins are often found as components of larger protein complexes...

    journal_title：ACS chemical biology

    pub_type： 杂志文章,评审

    doi：10.1021/cb500996u

    authors： Brand M,Measures AR,Wilson BG,Cortopassi WA,Alexander R,Höss M,Hewings DS,Rooney TP,Paton RS,Conway SJ

    更新日期：2015-01-16 00:00:00

  • CB-6644 Is a Selective Inhibitor of the RUVBL1/2 Complex with Anticancer Activity.

    abstract：:RUVBL1 and RUVBL2 are ATPases associated with diverse cellular activities (AAAs) that form a complex involved in a variety of cellular processes, including chromatin remodeling and regulation of gene expression. RUVBLs have a strong link to oncogenesis, where overexpression is correlated with tumor growth and poor pro...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/acschembio.8b00904

    authors： Assimon VA,Tang Y,Vargas JD,Lee GJ,Wu ZY,Lou K,Yao B,Menon MK,Pios A,Perez KC,Madriaga A,Buchowiecki PK,Rolfe M,Shawver L,Jiao X,Le Moigne R,Zhou HJ,Anderson DJ

    更新日期：2019-02-15 00:00:00

  • Approaches to Study Phosphatases.

    abstract：:Phosphatases play key roles in normal physiology and diseases. Studying phosphatases has been both essential and challenging, and the application of conventional genetic and biochemical methods has led to crucial but still limited understanding of their mechanisms, substrates, and exclusive functions within highly int...

    journal_title：ACS chemical biology

    pub_type： 杂志文章,评审

    doi：10.1021/acschembio.6b00570

    authors： Fahs S,Lujan P,Köhn M

    更新日期：2016-11-18 00:00:00

  • Progressive Stereo Locking (PSL): A Residual Dipolar Coupling Based Force Field Method for Determining the Relative Configuration of Natural Products and Other Small Molecules.

    abstract：:Establishing the relative configuration of a bioactive natural product represents the most challenging part in determining its structure. Residual dipolar couplings (RDCs) are sensitive probes of the relative spatial orientation of internuclear vectors. We adapted a force field structure calculation methodology to all...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/acschembio.7b00281

    authors： Cornilescu G,Ramos Alvarenga RF,Wyche TP,Bugni TS,Gil RR,Cornilescu CC,Westler WM,Markley JL,Schwieters CD

    更新日期：2017-08-18 00:00:00

  • Analysis of amyloid nanostructures using photo-cross-linking: in situ comparison of three widely used photo-cross-linkers.

    abstract：:Photoinduced cross-linking (PIC) has become a powerful tool in chemical biology for the identification and mapping of stable or transient interactions between biomacromolecules and their (unknown) ligands. However, the value of PIC for in vitro and in vivo structural proteomics can be realized only if cross-linking re...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb400731s

    authors： Preston GW,Radford SE,Ashcroft AE,Wilson AJ

    更新日期：2014-03-21 00:00:00

  • Cruentaren A binds F1F0 ATP synthase to modulate the Hsp90 protein folding machinery.

    abstract：:The molecular chaperone Hsp90 requires the assistance of immunophilins, co-chaperones, and partner proteins for the conformational maturation of client proteins. Hsp90 inhibition represents a promising anticancer strategy due to the dependence of numerous oncogenic signaling pathways upon Hsp90 function. Historically,...

    journal_title：ACS chemical biology

    pub_type： 杂志文章

    doi：10.1021/cb400906e

    authors： Hall JA,Kusuma BR,Brandt GE,Blagg BS

    更新日期：2014-04-18 00:00:00

  • Evolving sensitivity.

    abstract：:Engineering gene circuits with novel functions holds promise for broad applications in biology, engineering, and medicine. Directed evolution complements rational design as an important strategy for optimizing gene circuits and circuit elements. ...

    journal_title：ACS chemical biology

    pub_type： 评论,杂志文章,评审

    doi：10.1021/cb6004596

    authors： Song H,You L

    更新日期：2006-12-20 00:00:00