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| | ==Structure guided design and discovery of Indazole ethers as highly potent, non-steroidal Glucocorticoid receptor modulators== | | ==Structure guided design and discovery of Indazole ethers as highly potent, non-steroidal Glucocorticoid receptor modulators== |
| - | <StructureSection load='5g5w' size='340' side='right' caption='[[5g5w]], [[Resolution|resolution]] 2.20Å' scene=''> | + | <StructureSection load='5g5w' size='340' side='right'caption='[[5g5w]], [[Resolution|resolution]] 2.20Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5g5w]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5G5W OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5G5W FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5g5w]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5G5W OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5G5W FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=R8C:2,2,2-TRIFLUORO-N-[(1R,2S)-1-{[1-(4-FLUOROPHENYL)-1H-INDAZOL-5-YL]OXY}-1-PHENYLPROPAN-2-YL]ACETAMIDE'>R8C</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.2Å</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5g5w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5g5w OCA], [http://pdbe.org/5g5w PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5g5w RCSB], [http://www.ebi.ac.uk/pdbsum/5g5w PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5g5w ProSAT]</span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=R8C:2,2,2-TRIFLUORO-N-[(1R,2S)-1-{[1-(4-FLUOROPHENYL)-1H-INDAZOL-5-YL]OXY}-1-PHENYLPROPAN-2-YL]ACETAMIDE'>R8C</scene></td></tr> |
| | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5g5w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5g5w OCA], [https://pdbe.org/5g5w PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5g5w RCSB], [https://www.ebi.ac.uk/pdbsum/5g5w PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5g5w ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/GCR_HUMAN GCR_HUMAN]] Defects in NR3C1 are a cause of glucocorticoid resistance (GCRES) [MIM:[http://omim.org/entry/138040 138040]]; also known as cortisol resistance. It is a hypertensive, hyperandrogenic disorder characterized by increased serum cortisol concentrations. Inheritance is autosomal dominant.<ref>PMID:12050230</ref> <ref>PMID:1704018</ref> <ref>PMID:7683692</ref> <ref>PMID:11589680</ref> <ref>PMID:11701741</ref> [[http://www.uniprot.org/uniprot/NCOA2_HUMAN NCOA2_HUMAN]] Note=Chromosomal aberrations involving NCOA2 may be a cause of acute myeloid leukemias. Inversion inv(8)(p11;q13) generates the KAT6A-NCOA2 oncogene, which consists of the N-terminal part of KAT6A and the C-terminal part of NCOA2/TIF2. KAT6A-NCOA2 binds to CREBBP and disrupts its function in transcription activation. | + | [https://www.uniprot.org/uniprot/GCR_HUMAN GCR_HUMAN] Defects in NR3C1 are a cause of glucocorticoid resistance (GCRES) [MIM:[https://omim.org/entry/138040 138040]; also known as cortisol resistance. It is a hypertensive, hyperandrogenic disorder characterized by increased serum cortisol concentrations. Inheritance is autosomal dominant.<ref>PMID:12050230</ref> <ref>PMID:1704018</ref> <ref>PMID:7683692</ref> <ref>PMID:11589680</ref> <ref>PMID:11701741</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/GCR_HUMAN GCR_HUMAN]] Receptor for glucocorticoids (GC). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modulator of other transcription factors. Affects inflammatory responses, cellular proliferation and differentiation in target tissues. Could act as a coactivator for STAT5-dependent transcription upon growth hormone (GH) stimulation and could reveal an essential role of hepatic GR in the control of body growth. Involved in chromatin remodeling. Plays a significant role in transactivation.<ref>PMID:21664385</ref> [[http://www.uniprot.org/uniprot/NCOA2_HUMAN NCOA2_HUMAN]] Transcriptional coactivator for steroid receptors and nuclear receptors. Coactivator of the steroid binding domain (AF-2) but not of the modulating N-terminal domain (AF-1). Required with NCOA1 to control energy balance between white and brown adipose tissues.<ref>PMID:9430642</ref> | + | [https://www.uniprot.org/uniprot/GCR_HUMAN GCR_HUMAN] Receptor for glucocorticoids (GC). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modulator of other transcription factors. Affects inflammatory responses, cellular proliferation and differentiation in target tissues. Could act as a coactivator for STAT5-dependent transcription upon growth hormone (GH) stimulation and could reveal an essential role of hepatic GR in the control of body growth. Involved in chromatin remodeling. Plays a significant role in transactivation.<ref>PMID:21664385</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5g5w" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5g5w" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Glucocorticoid receptor 3D structures|Glucocorticoid receptor 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Berger, M]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Dahmen, J]] | + | [[Category: Large Structures]] |
| - | [[Category: Dearman, M]] | + | [[Category: Berger M]] |
| - | [[Category: Edman, K]] | + | [[Category: Dahmen J]] |
| - | [[Category: Eriksson, A]] | + | [[Category: Dearman M]] |
| - | [[Category: Hansson, T]] | + | [[Category: Edman K]] |
| - | [[Category: Hemmerling, M]] | + | [[Category: Eriksson A]] |
| - | [[Category: Hendrickx, R]] | + | [[Category: Hansson T]] |
| - | [[Category: Ivanova, S]] | + | [[Category: Hemmerling M]] |
| - | [[Category: Jellesmark-Jensen, T]] | + | [[Category: Hendrickx R]] |
| - | [[Category: Lepisto, M]] | + | [[Category: Ivanova S]] |
| - | [[Category: Rehwinkel, H]] | + | [[Category: Jellesmark-Jensen T]] |
| - | [[Category: Wissler, L]] | + | [[Category: Lepisto M]] |
| - | [[Category: Glucocorticoid receptor]]
| + | [[Category: Rehwinkel H]] |
| - | [[Category: Hormone]]
| + | [[Category: Wissler L]] |
| - | [[Category: Ligand complex]]
| + | |
| - | [[Category: Nuclear hormone receptor]]
| + | |
| - | [[Category: Peptide complex]]
| + | |
| - | [[Category: Signaling protein]]
| + | |
| - | [[Category: Steroid receptor]]
| + | |
| Structural highlights
Disease
GCR_HUMAN Defects in NR3C1 are a cause of glucocorticoid resistance (GCRES) [MIM:138040; also known as cortisol resistance. It is a hypertensive, hyperandrogenic disorder characterized by increased serum cortisol concentrations. Inheritance is autosomal dominant.[1] [2] [3] [4] [5]
Function
GCR_HUMAN Receptor for glucocorticoids (GC). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modulator of other transcription factors. Affects inflammatory responses, cellular proliferation and differentiation in target tissues. Could act as a coactivator for STAT5-dependent transcription upon growth hormone (GH) stimulation and could reveal an essential role of hepatic GR in the control of body growth. Involved in chromatin remodeling. Plays a significant role in transactivation.[6]
Publication Abstract from PubMed
A structure-based design approach led to the identification of a novel class of indazole ether based, non-steroidal glucocorticoid receptor (GR) modulators. Several examples were identified that displayed cell potency in the picomolar range, inhibiting LPS-induced TNF-alpha release by primary peripheral blood mononuclear cells (PBMCs). Additionally, an improved steroid hormone receptor binding selectivity profile, compared to classical steroidal GR agonists, was demonstrated. The indazole ether core tolerated a broad range of substituents allowing for modulation of the physiochemical parameters. A small sub-set of indazole ethers, with pharmacokinetic properties suitable for oral administration, was investigated in a rat antigen-induced joint inflammation model and demonstrated excellent anti-inflammatory efficacy.
Discovery of indazole ethers as novel, potent, non-steroidal glucocorticoid receptor modulators.,Hemmerling M, Edman K, Lepisto M, Eriksson A, Ivanova S, Dahmen J, Rehwinkel H, Berger M, Hendrickx R, Dearman M, Jensen TJ, Wissler L, Hansson T Bioorg Med Chem Lett. 2016 Dec 1;26(23):5741-5748. doi:, 10.1016/j.bmcl.2016.10.052. Epub 2016 Oct 19. PMID:27810243[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Vottero A, Kino T, Combe H, Lecomte P, Chrousos GP. A novel, C-terminal dominant negative mutation of the GR causes familial glucocorticoid resistance through abnormal interactions with p160 steroid receptor coactivators. J Clin Endocrinol Metab. 2002 Jun;87(6):2658-67. PMID:12050230
- ↑ Hurley DM, Accili D, Stratakis CA, Karl M, Vamvakopoulos N, Rorer E, Constantine K, Taylor SI, Chrousos GP. Point mutation causing a single amino acid substitution in the hormone binding domain of the glucocorticoid receptor in familial glucocorticoid resistance. J Clin Invest. 1991 Feb;87(2):680-6. PMID:1704018 doi:http://dx.doi.org/10.1172/JCI115046
- ↑ Malchoff DM, Brufsky A, Reardon G, McDermott P, Javier EC, Bergh CH, Rowe D, Malchoff CD. A mutation of the glucocorticoid receptor in primary cortisol resistance. J Clin Invest. 1993 May;91(5):1918-25. PMID:7683692 doi:http://dx.doi.org/10.1172/JCI116410
- ↑ Ruiz M, Lind U, Gafvels M, Eggertsen G, Carlstedt-Duke J, Nilsson L, Holtmann M, Stierna P, Wikstrom AC, Werner S. Characterization of two novel mutations in the glucocorticoid receptor gene in patients with primary cortisol resistance. Clin Endocrinol (Oxf). 2001 Sep;55(3):363-71. PMID:11589680
- ↑ Kino T, Stauber RH, Resau JH, Pavlakis GN, Chrousos GP. Pathologic human GR mutant has a transdominant negative effect on the wild-type GR by inhibiting its translocation into the nucleus: importance of the ligand-binding domain for intracellular GR trafficking. J Clin Endocrinol Metab. 2001 Nov;86(11):5600-8. PMID:11701741
- ↑ Psarra AM, Sekeris CE. Glucocorticoids induce mitochondrial gene transcription in HepG2 cells: role of the mitochondrial glucocorticoid receptor. Biochim Biophys Acta. 2011 Oct;1813(10):1814-21. doi:, 10.1016/j.bbamcr.2011.05.014. Epub 2011 Jun 2. PMID:21664385 doi:10.1016/j.bbamcr.2011.05.014
- ↑ Hemmerling M, Edman K, Lepisto M, Eriksson A, Ivanova S, Dahmen J, Rehwinkel H, Berger M, Hendrickx R, Dearman M, Jensen TJ, Wissler L, Hansson T. Discovery of indazole ethers as novel, potent, non-steroidal glucocorticoid receptor modulators. Bioorg Med Chem Lett. 2016 Dec 1;26(23):5741-5748. doi:, 10.1016/j.bmcl.2016.10.052. Epub 2016 Oct 19. PMID:27810243 doi:http://dx.doi.org/10.1016/j.bmcl.2016.10.052
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