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  • 1
    Publication Date: 2011-09-06
    Description: PPARgamma is the functioning receptor for the thiazolidinedione (TZD) class of antidiabetes drugs including rosiglitazone and pioglitazone. These drugs are full classical agonists for this nuclear receptor, but recent data have shown that many PPARgamma-based drugs have a separate biochemical activity, blocking the obesity-linked phosphorylation of PPARgamma by Cdk5. Here we describe novel synthetic compounds that have a unique mode of binding to PPARgamma, completely lack classical transcriptional agonism and block the Cdk5-mediated phosphorylation in cultured adipocytes and in insulin-resistant mice. Moreover, one such compound, SR1664, has potent antidiabetic activity while not causing the fluid retention and weight gain that are serious side effects of many of the PPARgamma drugs. Unlike TZDs, SR1664 also does not interfere with bone formation in culture. These data illustrate that new classes of antidiabetes drugs can be developed by specifically targeting the Cdk5-mediated phosphorylation of PPARgamma.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3179551/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3179551/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Choi, Jang Hyun -- Banks, Alexander S -- Kamenecka, Theodore M -- Busby, Scott A -- Chalmers, Michael J -- Kumar, Naresh -- Kuruvilla, Dana S -- Shin, Youseung -- He, Yuanjun -- Bruning, John B -- Marciano, David P -- Cameron, Michael D -- Laznik, Dina -- Jurczak, Michael J -- Schurer, Stephan C -- Vidovic, Dusica -- Shulman, Gerald I -- Spiegelman, Bruce M -- Griffin, Patrick R -- 1RC4DK090861/DK/NIDDK NIH HHS/ -- DK31405/DK/NIDDK NIH HHS/ -- R01 DK040936/DK/NIDDK NIH HHS/ -- R01 GM084041/GM/NIGMS NIH HHS/ -- R01 GM084041-03/GM/NIGMS NIH HHS/ -- R01-GM084041/GM/NIGMS NIH HHS/ -- R37 DK031405/DK/NIDDK NIH HHS/ -- R37 DK031405-30/DK/NIDDK NIH HHS/ -- R37 DK031405-31/DK/NIDDK NIH HHS/ -- RC4 DK090861/DK/NIDDK NIH HHS/ -- RC4 DK090861-01/DK/NIDDK NIH HHS/ -- S10 RR027270/RR/NCRR NIH HHS/ -- U24 DK059635/DK/NIDDK NIH HHS/ -- U54 MH074404/MH/NIMH NIH HHS/ -- U54 MH074404-01/MH/NIMH NIH HHS/ -- U54-MH074404/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- Intramural NIH HHS/ -- England -- Nature. 2011 Sep 4;477(7365):477-81. doi: 10.1038/nature10383.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cancer Biology and Division of Metabolism and Chronic Disease, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21892191" target="_blank"〉PubMed〈/a〉
    Keywords: 3T3-L1 Cells ; Adipocytes/drug effects/metabolism ; Adipose Tissue, White/drug effects/metabolism ; Animals ; Biphenyl Compounds/chemistry/pharmacology ; Body Fluids/drug effects ; COS Cells ; Cercopithecus aethiops ; Cyclin-Dependent Kinase 5/*antagonists & inhibitors ; Dietary Fats/pharmacology ; Disease Models, Animal ; Dose-Response Relationship, Drug ; HEK293 Cells ; Humans ; Hypoglycemic Agents/adverse effects/chemistry/*pharmacology ; Ligands ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Obese ; Models, Molecular ; Obesity/chemically induced/metabolism ; Osteogenesis/drug effects ; PPAR gamma/agonists/chemistry/*metabolism ; Phosphorylation/drug effects ; Phosphoserine/metabolism ; Thiazolidinediones/adverse effects/pharmacology ; Transcription, Genetic/drug effects ; Tumor Necrosis Factor-alpha/pharmacology ; Weight Gain/drug effects
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2011-04-19
    Description: T-helper cells that produce interleukin-17 (T(H)17 cells) are a recently identified CD4(+) T-cell subset with characterized pathological roles in autoimmune diseases. The nuclear receptors retinoic-acid-receptor-related orphan receptors alpha and gammat (RORalpha and RORgammat, respectively) have indispensible roles in the development of this cell type. Here we present SR1001, a high-affinity synthetic ligand-the first in a new class of compound-that is specific to both RORalpha and RORgammat and which inhibits T(H)17 cell differentiation and function. SR1001 binds specifically to the ligand-binding domains of RORalpha and RORgammat, inducing a conformational change within the ligand-binding domain that encompasses the repositioning of helix 12 and leads to diminished affinity for co-activators and increased affinity for co-repressors, resulting in suppression of the receptors' transcriptional activity. SR1001 inhibited the development of murine T(H)17 cells, as demonstrated by inhibition of interleukin-17A gene expression and protein production. Furthermore, SR1001 inhibited the expression of cytokines when added to differentiated murine or human T(H)17 cells. Finally, SR1001 effectively suppressed the clinical severity of autoimmune disease in mice. Our data demonstrate the feasibility of targeting the orphan receptors RORalpha and RORgammat to inhibit specifically T(H)17 cell differentiation and function, and indicate that this novel class of compound has potential utility in the treatment of autoimmune diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148894/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148894/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Solt, Laura A -- Kumar, Naresh -- Nuhant, Philippe -- Wang, Yongjun -- Lauer, Janelle L -- Liu, Jin -- Istrate, Monica A -- Kamenecka, Theodore M -- Roush, William R -- Vidovic, Dusica -- Schurer, Stephan C -- Xu, Jihong -- Wagoner, Gail -- Drew, Paul D -- Griffin, Patrick R -- Burris, Thomas P -- DK080201/DK/NIDDK NIH HHS/ -- DK088499/DK/NIDDK NIH HHS/ -- DK089984/DK/NIDDK NIH HHS/ -- GM084041/GM/NIGMS NIH HHS/ -- MH084512/MH/NIMH NIH HHS/ -- R01 DK080201/DK/NIDDK NIH HHS/ -- R01 DK080201-06/DK/NIDDK NIH HHS/ -- R01 GM084041/GM/NIGMS NIH HHS/ -- R01 MH092769/MH/NIMH NIH HHS/ -- U54 MH084512/MH/NIMH NIH HHS/ -- U54 MH084512-02/MH/NIMH NIH HHS/ -- U54MH074404/MH/NIMH NIH HHS/ -- England -- Nature. 2011 Apr 28;472(7344):491-4. doi: 10.1038/nature10075. Epub 2011 Apr 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21499262" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autoimmunity/*drug effects/immunology ; Cell Differentiation/*drug effects ; Drug Inverse Agonism ; HEK293 Cells ; Humans ; Interleukin-17/biosynthesis/immunology ; Interleukins/biosynthesis/immunology ; Ligands ; Mice ; Mice, Inbred C57BL ; Models, Molecular ; Nuclear Receptor Subfamily 1, Group F, Member 1/antagonists & ; inhibitors/genetics/metabolism ; Nuclear Receptor Subfamily 1, Group F, Member 3/antagonists & ; inhibitors/genetics/metabolism ; Sulfonamides/*pharmacology ; Th17 Cells/*cytology/drug effects/*immunology/secretion ; Thiazoles/*pharmacology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2017-11-23
    Description: The Journal of Organic Chemistry DOI: 10.1021/acs.joc.7b02169
    Print ISSN: 0022-3263
    Electronic ISSN: 1520-6904
    Topics: Chemistry and Pharmacology
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  • 4
    ISSN: 1432-1211
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract  Mutant mice generated by disrupting the H2-Aa b major histocompatibility complex (Mhc) gene are demonstrated here to express Aβb chains in the absence of α chains. These mice possess a CD4+ helper T cell (Th) repertoire that uses predominantly the Vβ7 T-cell antigen receptor (Tcr) segment for recognition of any protein antigen presented by the α-free Aβ molecule. As an alloantigen, the Aα-free Aβ molecule is recognized very poorly by T cells from a series of class II disparate mouse strains, indicating that it is grossly different from normal α/β heterodimers. Indeed, molecular modeling suggests a β/β homodimer arrangement with an altered geometry of the Tcr contact area. Interestingly, the mutant mice exhibit normal alloreactivity, without a restricted Vβ usage, toward a series of foreign α/β class II heterodimers, although their T cells developed in the absence of such heterodimers. Thus, the complementarity of Tcr to normal α/β heterodimers, and thereby also alloreactivity, appears to be an ontogeny independent (i. e., germline-encoded) feature.
    Type of Medium: Electronic Resource
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  • 5
    Publication Date: 2017-01-05
    Description: The ‘druggable genome’ encompasses several protein families, but only a subset of targets within them have attracted significant research attention and thus have information about them publicly available. The Illuminating the Druggable Genome (IDG) program was initiated in 2014, has the goal of developing experimental techniques and a Knowledge Management Center (KMC) that would collect and organize information about protein targets from four families, representing the most common druggable targets with an emphasis on understudied proteins. Here, we describe two resources developed by the KMC: the Target Central Resource Database (TCRD) which collates many heterogeneous gene/protein datasets and Pharos ( https://pharos.nih.gov ), a multimodal web interface that presents the data from TCRD. We briefly describe the types and sources of data considered by the KMC and then highlight features of the Pharos interface designed to enable intuitive access to the IDG knowledgebase. The aim of Pharos is to encourage ‘serendipitous browsing’, whereby related, relevant information is made easily discoverable. We conclude by describing two use cases that highlight the utility of Pharos and TCRD.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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