Publications by authors named "Anne-Marie Michon"

22 Publications

  • Page 1 of 1

GSK973 Is an Inhibitor of the Second Bromodomains (BD2s) of the Bromodomain and Extra-Terminal (BET) Family.

ACS Med Chem Lett 2020 Aug 6;11(8):1581-1587. Epub 2020 Jul 6.

Epigenetics Discovery Performance Unit and Platform Technology and Science, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.

Pan-BET inhibitors have shown profound efficacy in a number of in vivo preclinical models and have entered the clinic in oncology trials where adverse events have been reported. These inhibitors interact equipotently with the eight bromodomains of the BET family of proteins. To better understand the contribution of each domain to their efficacy and to improve from their safety profile, selective inhibitors are required. This Letter discloses the profile of GSK973, a highly selective inhibitor of the second bromodomains of the BET proteins that has undergone extensive preclinical in vitro and in vivo characterization.
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http://dx.doi.org/10.1021/acsmedchemlett.0c00247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429977PMC
August 2020

The Optimization of a Novel, Weak Bromo and Extra Terminal Domain (BET) Bromodomain Fragment Ligand to a Potent and Selective Second Bromodomain (BD2) Inhibitor.

J Med Chem 2020 09 30;63(17):9093-9126. Epub 2020 Aug 30.

IVIVT Cellzome, Platform Technology and Science, GlaxoSmithKline, Meyerhofstrasse 1, 69117 Heidelberg, Germany.

The profound efficacy, yet associated toxicity of pan-BET inhibitors is well documented. The possibility of an ameliorated safety profile driven by significantly selective (>100-fold) inhibition of a subset of the eight bromodomains is enticing, but challenging given the close homology. Herein, we describe the X-ray crystal structure-directed optimization of a novel weak fragment ligand with a pan-second bromodomain (BD2) bias, to potent and highly BD2 selective inhibitors. A template hopping approach, enabled by our parallel research into an orthogonal template (, GSK046), was the basis for the high selectivity observed. This culminated in two tool molecules, (GSK620) and (GSK549), which showed an anti-inflammatory phenotype in human whole blood, confirming their cellular target engagement. Excellent broad selectivity, developability, and in vivo oral pharmacokinetics characterize these tools, which we hope will be of broad utility to the field of epigenetics research.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00796DOI Listing
September 2020

Design and Synthesis of a Highly Selective and -Capable Inhibitor of the Second Bromodomain of the Bromodomain and Extra Terminal Domain Family of Proteins.

J Med Chem 2020 09 20;63(17):9070-9092. Epub 2020 Aug 20.

Epigenetics Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K.

Pan-bromodomain and extra terminal domain (BET) inhibitors interact equipotently with the eight bromodomains of the BET family of proteins and have shown profound efficacy in a number of phenotypic assays and pre-clinical models in inflammation or oncology. A number of these inhibitors have progressed to the clinic where pharmacology-driven adverse events have been reported. To better understand the contribution of each domain to their efficacy and improve their safety profile, selective inhibitors are required. This article discloses the profile of GSK046, also known as iBET-BD2, a highly selective inhibitor of the second bromodomains of the BET proteins that has undergone extensive pre-clinical and characterization.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00605DOI Listing
September 2020

Application of Atypical Acetyl-lysine Methyl Mimetics in the Development of Selective Inhibitors of the Bromodomain-Containing Protein 7 (BRD7)/Bromodomain-Containing Protein 9 (BRD9) Bromodomains.

J Med Chem 2020 06 29;63(11):5816-5840. Epub 2020 May 29.

GlaxoSmithKline R&D, Stevenage SG1 2NY, Hertfordshire, United Kingdom.

Non-BET bromodomain-containing proteins have become attractive targets for the development of novel therapeutics targeting epigenetic pathways. To help facilitate the target validation of this class of proteins, structurally diverse small-molecule ligands and methodologies to produce selective inhibitors in a predictable fashion are in high demand. Herein, we report the development and application of atypical acetyl-lysine (KAc) methyl mimetics to take advantage of the differential stability of conserved water molecules in the bromodomain binding site. Discovery of the -butyl group as an atypical KAc methyl mimetic allowed generation of (GSK6776) as a soluble, permeable, and selective BRD7/9 inhibitor from a pyridazinone template. The -butyl group was then used to enhance the bromodomain selectivity of an existing BRD9 inhibitor and to transform pan-bromodomain inhibitors into BRD7/9 selective compounds. Finally, a solvent-exposed vector was defined from the pyridazinone template to enable bifunctional molecule synthesis, and affinity enrichment chemoproteomic experiments were used to confirm several of the endogenous protein partners of BRD7 and BRD9, which form part of the chromatin remodeling PBAF and BAF complexes, respectively.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00075DOI Listing
June 2020

Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation.

Science 2020 04 19;368(6489):387-394. Epub 2020 Mar 19.

Cellzome GmbH, Functional Genomics R&D, GlaxoSmithKline, Heidelberg, Germany.

The two tandem bromodomains of the BET (bromodomain and extraterminal domain) proteins enable chromatin binding to facilitate transcription. Drugs that inhibit both bromodomains equally have shown efficacy in certain malignant and inflammatory conditions. To explore the individual functional contributions of the first (BD1) and second (BD2) bromodomains in biology and therapy, we developed selective BD1 and BD2 inhibitors. We found that steady-state gene expression primarily requires BD1, whereas the rapid increase of gene expression induced by inflammatory stimuli requires both BD1 and BD2 of all BET proteins. BD1 inhibitors phenocopied the effects of pan-BET inhibitors in cancer models, whereas BD2 inhibitors were predominantly effective in models of inflammatory and autoimmune disease. These insights into the differential requirement of BD1 and BD2 for the maintenance and induction of gene expression may guide future BET-targeted therapies.
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http://dx.doi.org/10.1126/science.aaz8455DOI Listing
April 2020

Biological plasticity rescues target activity in CRISPR knock outs.

Nat Methods 2019 11 28;16(11):1087-1093. Epub 2019 Oct 28.

European Molecular Biology Laboratory, Heidelberg, Germany.

Gene knock outs (KOs) are efficiently engineered through CRISPR-Cas9-induced frameshift mutations. While the efficiency of DNA editing is readily verified by DNA sequencing, a systematic understanding of the efficiency of protein elimination has been lacking. Here we devised an experimental strategy combining RNA sequencing and triple-stage mass spectrometry to characterize 193 genetically verified deletions targeting 136 distinct genes generated by CRISPR-induced frameshifts in HAP1 cells. We observed residual protein expression for about one third of the quantified targets, at variable levels from low to original, and identified two causal mechanisms, translation reinitiation leading to N-terminally truncated target proteins or skipping of the edited exon leading to protein isoforms with internal sequence deletions. Detailed analysis of three truncated targets, BRD4, DNMT1 and NGLY1, revealed partial preservation of protein function. Our results imply that systematic characterization of residual protein expression or function in CRISPR-Cas9-generated KO lines is necessary for phenotype interpretation.
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http://dx.doi.org/10.1038/s41592-019-0614-5DOI Listing
November 2019

A Qualified Success: Discovery of a New Series of ATAD2 Bromodomain Inhibitors with a Novel Binding Mode Using High-Throughput Screening and Hit Qualification.

J Med Chem 2019 08 9;62(16):7506-7525. Epub 2019 Aug 9.

GlaxoSmithKline Tres Cantos , 28760 Tres Cantos , Madrid , Spain.

The bromodomain of ATAD2 has proved to be one of the least-tractable proteins within this target class. Here, we describe the discovery of a new class of inhibitors by high-throughput screening and show how the difficulties encountered in establishing a screening triage capable of finding progressible hits were overcome by data-driven optimization. Despite the prevalence of nonspecific hits and an exceptionally low progressible hit rate (0.001%), our optimized hit qualification strategy employing orthogonal biophysical methods enabled us to identify a single active series. The compounds have a novel ATAD2 binding mode with noncanonical features including the displacement of all conserved water molecules within the active site and a halogen-bonding interaction. In addition to reporting this new series and preliminary structure-activity relationship, we demonstrate the value of diversity screening to complement the knowledge-based approach used in our previous ATAD2 work. We also exemplify tactics that can increase the chance of success when seeking new chemical starting points for novel and less-tractable targets.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00673DOI Listing
August 2019

A Rasmussen encephalitis, autoimmune encephalitis, and mitochondrial disease mimicker: expanding the DNM1L-associated intractable epilepsy and encephalopathy phenotype.

Epileptic Disord 2019 Feb;21(1):112-116

Department of Pediatric Epilepsy, Beaumont Health, Royal Oak, MI 48073.

Dynamin-1-like protein (DNM1L) gene variants have been linked to childhood refractory epilepsy, developmental delay, encephalopathy, microcephaly, and progressive diffuse cerebral atrophy. However, only a few cases have been reported in the literature and there is still a limited amount of information about the symptomatology and pathophysiology associated with pathogenic variants of DNM1L. We report a 10-year-old girl with a one-year history of mild learning disorder and absence seizures who presented with new-onset focal status epilepticus which progressed to severe encephalopathy and asymmetric hemispheric cerebral atrophy. Differential diagnosis included mitochondrial disease, Rasmussen's encephalitis, and autoimmune encephalitis. Disease progressed from one hemisphere to the other despite anti-seizure medications, hemispherectomy, vagus nerve stimulator, ketogenic diet, and immunomodulators. Continued cerebral atrophy and refractory seizures evolved until death four years after initial presentation. Post-mortem whole-exome sequencing revealed a pathogenic DNM1L variant. This paper presents a novel case of adolescent-onset DNM1L-related intractable epilepsy and encephalopathy.
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http://dx.doi.org/10.1684/epd.2019.1036DOI Listing
February 2019

Aiming to Miss a Moving Target: Bromo and Extra Terminal Domain (BET) Selectivity in Constrained ATAD2 Inhibitors.

J Med Chem 2018 09 18;61(18):8321-8336. Epub 2018 Sep 18.

Molecular Discovery Research, Cellzome GmbH , GlaxoSmithKline , Meyerhofstrasse 1 , 69117 Heidelberg , Germany.

ATAD2 is a cancer-associated protein whose bromodomain has been described as among the least druggable of its class. In our recent disclosure of the first chemical probe against this bromodomain, GSK8814 (6), we described the use of a conformationally constrained methoxy piperidine to gain selectivity over the BET bromodomains. Here we describe an orthogonal conformational restriction strategy of the piperidine ring to give potent and selective tropane inhibitors and show structural insights into why this was more challenging than expected. Greater understanding of why different rational approaches succeeded or failed should help in the future design of selectivity in the bromodomain family.
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http://dx.doi.org/10.1021/acs.jmedchem.8b00862DOI Listing
September 2018

Discovery of a Potent, Cell Penetrant, and Selective p300/CBP-Associated Factor (PCAF)/General Control Nonderepressible 5 (GCN5) Bromodomain Chemical Probe.

J Med Chem 2017 01 9;60(2):695-709. Epub 2017 Jan 9.

WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde , Thomas Graham Building, 295 Cathedral Street, Glasgow, G1 1XL, United Kingdom.

p300/CREB binding protein associated factor (PCAF/KAT2B) and general control nonderepressible 5 (GCN5/KAT2A) are multidomain proteins that have been implicated in retroviral infection, inflammation pathways, and cancer development. However, outside of viral replication, little is known about the dependence of these effects on the C-terminal bromodomain. Herein, we report GSK4027 as a chemical probe for the PCAF/GCN5 bromodomain, together with GSK4028 as an enantiomeric negative control. The probe was optimized from a weakly potent, nonselective pyridazinone hit to deliver high potency for the PCAF/GCN5 bromodomain, high solubility, cellular target engagement, and ≥18000-fold selectivity over the BET family, together with ≥70-fold selectivity over the wider bromodomain families.
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http://dx.doi.org/10.1021/acs.jmedchem.6b01566DOI Listing
January 2017

A Chemical Probe for the ATAD2 Bromodomain.

Angew Chem Int Ed Engl 2016 09 17;55(38):11382-6. Epub 2016 Aug 17.

GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK.

ATAD2 is a cancer-associated protein whose bromodomain has been described as among the least druggable of that target class. Starting from a potent lead, permeability and selectivity were improved through a dual approach: 1) using CF2 as a sulfone bio-isostere to exploit the unique properties of fluorine, and 2) using 1,3-interactions to control the conformation of a piperidine ring. This resulted in the first reported low-nanomolar, selective and cell permeable chemical probe for ATAD2.
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http://dx.doi.org/10.1002/anie.201603928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314595PMC
September 2016

GSK6853, a Chemical Probe for Inhibition of the BRPF1 Bromodomain.

ACS Med Chem Lett 2016 Jun 9;7(6):552-7. Epub 2016 May 9.

Epinova Discovery Performance Unit, Quantitative Pharmacology, Experimental Medicine Unit, Flexible Discovery Unit, and Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.

The BRPF (Bromodomain and PHD Finger-containing) protein family are important scaffolding proteins for assembly of MYST histone acetyltransferase complexes. A selective benzimidazolone BRPF1 inhibitor showing micromolar activity in a cellular target engagement assay was recently described. Herein, we report the optimization of this series leading to the identification of a superior BRPF1 inhibitor suitable for in vivo studies.
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http://dx.doi.org/10.1021/acsmedchemlett.6b00092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4904261PMC
June 2016

Structure-Based Optimization of Naphthyridones into Potent ATAD2 Bromodomain Inhibitors.

J Med Chem 2015 Aug 31;58(15):6151-78. Epub 2015 Jul 31.

∥Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline, Meyerhofstrasse 1, 69117 Heidelberg, Germany.

ATAD2 is a bromodomain-containing protein whose overexpression is linked to poor outcomes in a number of different cancer types. To date, no potent and selective inhibitors of the bromodomain have been reported. This article describes the structure-based optimization of a series of naphthyridones from micromolar leads with no selectivity over the BET bromodomains to inhibitors with sub-100 nM ATAD2 potency and 100-fold BET selectivity.
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http://dx.doi.org/10.1021/acs.jmedchem.5b00773DOI Listing
August 2015

Fragment-Based Discovery of Low-Micromolar ATAD2 Bromodomain Inhibitors.

J Med Chem 2015 Jul 9;58(14):5649-73. Epub 2015 Jul 9.

∥Drug Metabolism and Pharmacokinetics (DMPK), GlaxoSmithKline, Park Road, Ware, Hertfordshire SG12 0DP, United Kingdom.

Overexpression of ATAD2 (ATPase family, AAA domain containing 2) has been linked to disease severity and progression in a wide range of cancers, and is implicated in the regulation of several drivers of cancer growth. Little is known of the dependence of these effects upon the ATAD2 bromodomain, which has been categorized as among the least tractable of its class. The absence of any potent, selective inhibitors limits clear understanding of the therapeutic potential of the bromodomain. Here, we describe the discovery of a hit from a fragment-based targeted array. Optimization of this produced the first known micromolar inhibitors of the ATAD2 bromodomain.
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http://dx.doi.org/10.1021/acs.jmedchem.5b00772DOI Listing
July 2015

Discovery of I-BRD9, a Selective Cell Active Chemical Probe for Bromodomain Containing Protein 9 Inhibition.

J Med Chem 2016 Feb 30;59(4):1425-39. Epub 2015 Apr 30.

Epinova Discovery Performance Unit, GlaxoSmithKline R&D , Stevenage, Hertfordshire SG1 2NY, U.K.

Acetylation of histone lysine residues is one of the most well-studied post-translational modifications of chromatin, selectively recognized by bromodomain "reader" modules. Inhibitors of the bromodomain and extra terminal domain (BET) family of bromodomains have shown profound anticancer and anti-inflammatory properties, generating much interest in targeting other bromodomain-containing proteins for disease treatment. Herein, we report the discovery of I-BRD9, the first selective cellular chemical probe for bromodomain-containing protein 9 (BRD9). I-BRD9 was identified through structure-based design, leading to greater than 700-fold selectivity over the BET family and 200-fold over the highly homologous bromodomain-containing protein 7 (BRD7). I-BRD9 was used to identify genes regulated by BRD9 in Kasumi-1 cells involved in oncology and immune response pathways and to the best of our knowledge, represents the first selective tool compound available to elucidate the cellular phenotype of BRD9 bromodomain inhibition.
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http://dx.doi.org/10.1021/acs.jmedchem.5b00256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354103PMC
February 2016

1,3-Dimethyl Benzimidazolones Are Potent, Selective Inhibitors of the BRPF1 Bromodomain.

ACS Med Chem Lett 2014 Nov 10;5(11):1190-5. Epub 2014 Sep 10.

Epinova Discovery Performance Unit and Molecular Discovery Research, GlaxoSmithKline , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.

The BRPF (bromodomain and PHD finger-containing) protein family are important scaffolding proteins for assembly of MYST histone acetyltransferase complexes. Here, we report the discovery, binding mode, and structure-activity relationship (SAR) of the first potent, selective series of inhibitors of the BRPF1 bromodomain.
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http://dx.doi.org/10.1021/ml5002932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4233354PMC
November 2014

Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes.

Nat Biotechnol 2011 Mar 23;29(3):255-65. Epub 2011 Jan 23.

Cellzome AG, Heidelberg, Germany.

The development of selective histone deacetylase (HDAC) inhibitors with anti-cancer and anti-inflammatory properties remains challenging in large part owing to the difficulty of probing the interaction of small molecules with megadalton protein complexes. A combination of affinity capture and quantitative mass spectrometry revealed the selectivity with which 16 HDAC inhibitors target multiple HDAC complexes scaffolded by ELM-SANT domain subunits, including a novel mitotic deacetylase complex (MiDAC). Inhibitors clustered according to their target profiles with stronger binding of aminobenzamides to the HDAC NCoR complex than to the HDAC Sin3 complex. We identified several non-HDAC targets for hydroxamate inhibitors. HDAC inhibitors with distinct profiles have correspondingly different effects on downstream targets. We also identified the anti-inflammatory drug bufexamac as a class IIb (HDAC6, HDAC10) HDAC inhibitor. Our approach enables the discovery of novel targets and inhibitors and suggests that the selectivity of HDAC inhibitors should be evaluated in the context of HDAC complexes and not purified catalytic subunits.
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http://dx.doi.org/10.1038/nbt.1759DOI Listing
March 2011

Proteome survey reveals modularity of the yeast cell machinery.

Nature 2006 Mar 22;440(7084):631-6. Epub 2006 Jan 22.

Cellzome AG, Meyerhofstrasse 1, 69117 Heidelberg, Germany.

Protein complexes are key molecular entities that integrate multiple gene products to perform cellular functions. Here we report the first genome-wide screen for complexes in an organism, budding yeast, using affinity purification and mass spectrometry. Through systematic tagging of open reading frames (ORFs), the majority of complexes were purified several times, suggesting screen saturation. The richness of the data set enabled a de novo characterization of the composition and organization of the cellular machinery. The ensemble of cellular proteins partitions into 491 complexes, of which 257 are novel, that differentially combine with additional attachment proteins or protein modules to enable a diversification of potential functions. Support for this modular organization of the proteome comes from integration with available data on expression, localization, function, evolutionary conservation, protein structure and binary interactions. This study provides the largest collection of physically determined eukaryotic cellular machines so far and a platform for biological data integration and modelling.
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http://dx.doi.org/10.1038/nature04532DOI Listing
March 2006

Use of levetiracetam to treat tics in children and adolescents with Tourette syndrome.

Mov Disord 2005 Jun;20(6):714-8

Department of Pediatrics, Oakwood Healthcare System, University of Michigan Medical School, 21031 Michigan Avenue, Dearborn, MI 48124, USA.

Some drugs currently used to treat tics in pediatric patients have drawbacks, including the risk of side effects. New therapeutic options with better safety profiles are needed. Levetiracetam is an antiepileptic drug with atypical mechanisms of action that might be beneficial for this indication. We evaluated the effects of levetiracetam on motor and vocal tics, behavior, and school performance in children and adolescents with tics and Tourette syndrome (TS). Sixty patients, < or =18 years of age, with tics and TS were enrolled in this prospective, open-label study. The initial starting dose of levetiracetam was 250 mg/day. The dosage was titrated over 3 weeks to 1,000 to 2,000 mg/day. Clinical outcomes were assessed with the Clinical Global Impression Scale, Yale Global Tic Severity Scale, and Revised Conners' Parent Rating Scale. Behavior and school performance were also recorded. All 60 patients showed improvements based on all of the scales used, and 43 patients improved with regard to behavior and school performance. Levetiracetam was generally well tolerated. Three patients discontinued treatment because of exaggeration of preexisting behavioral problems. Levetiracetam may be useful in treating tics in children and adolescents. Given its established safety profile, levetiracetam is a candidate for evaluation in a well-controlled trial.
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http://dx.doi.org/10.1002/mds.20385DOI Listing
June 2005

A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway.

Nat Cell Biol 2004 Feb 25;6(2):97-105. Epub 2004 Jan 25.

Cellzome AG, Meyerhofstrasse 1, 69117 Heidelberg, Germany.

Signal transduction pathways are modular composites of functionally interdependent sets of proteins that act in a coordinated fashion to transform environmental information into a phenotypic response. The pro-inflammatory cytokine tumour necrosis factor (TNF)-alpha triggers a signalling cascade, converging on the activation of the transcription factor NF-kappa B, which forms the basis for numerous physiological and pathological processes. Here we report the mapping of a protein interaction network around 32 known and candidate TNF-alpha/NF-kappa B pathway components by using an integrated approach comprising tandem affinity purification, liquid-chromatography tandem mass spectrometry, network analysis and directed functional perturbation studies using RNA interference. We identified 221 molecular associations and 80 previously unknown interactors, including 10 new functional modulators of the pathway. This systems approach provides significant insight into the logic of the TNF-alpha/NF-kappa B pathway and is generally applicable to other pathways relevant to human disease.
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http://dx.doi.org/10.1038/ncb1086DOI Listing
February 2004

Functional assessment following intrathecal baclofen therapy in children with spastic cerebral palsy.

J Child Neurol 2003 Jan;18(1):26-34

Neurology Division, Movement Disorder Clinic, Children's Hospital of Michigan, Wayne State University, School of Medicine, Detroit, MI, USA.

The purpose of this article is to describe outcomes of intrathecal baclofen therapy for 29 patients with cerebral palsy, focusing on impairments, functional limitations, and disability. Patients received individualized rehabilitation and were followed up to 24 months. The primary outcome measures were the Ashworth Scale and the functional skills and caregiver assistance scales of the Pediatric Evaluation of Disability Inventory (PEDI). Ashworth Scale scores were significantly reduced (P < or = .0005). All areas of functional skills and caregiver assistance improved. Comparing groups of adults and patients less than 18 years, there were no significant differences, but there was a relationship between age and dose. Comparing groups of patients in high and low levels of independent functional mobility, no significant differences were found. These results provide suggestive evidence that the combination of intrathecal baclofen therapy and rehabilitation has positive effects across the dimensions of disablement. This study serves as a basis for high-level scientific studies of these effects.
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http://dx.doi.org/10.1177/08830738030180010701DOI Listing
January 2003

Functional organization of the yeast proteome by systematic analysis of protein complexes.

Nature 2002 Jan;415(6868):141-7

Cellzome AG, Meyerhofstrasse 1, 69117 Heidelberg, Germany.

Most cellular processes are carried out by multiprotein complexes. The identification and analysis of their components provides insight into how the ensemble of expressed proteins (proteome) is organized into functional units. We used tandem-affinity purification (TAP) and mass spectrometry in a large-scale approach to characterize multiprotein complexes in Saccharomyces cerevisiae. We processed 1,739 genes, including 1,143 human orthologues of relevance to human biology, and purified 589 protein assemblies. Bioinformatic analysis of these assemblies defined 232 distinct multiprotein complexes and proposed new cellular roles for 344 proteins, including 231 proteins with no previous functional annotation. Comparison of yeast and human complexes showed that conservation across species extends from single proteins to their molecular environment. Our analysis provides an outline of the eukaryotic proteome as a network of protein complexes at a level of organization beyond binary interactions. This higher-order map contains fundamental biological information and offers the context for a more reasoned and informed approach to drug discovery.
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http://dx.doi.org/10.1038/415141aDOI Listing
January 2002