4csj: Difference between revisions

Revision as of 06:59, 21 May 2014

The discovery of potent selective glucocorticoid receptor modulators, suitable for inhalation

Structural highlights

4csj is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	EDO, NN7
Resources:	FirstGlance, OCA, RCSB, PDBsum

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

We report the discovery of highly potent and selective non-steroidal glucocorticoid receptor modulators with PK properties suitable for inhalation. A high throughput screen of the AstraZeneca compound collection identified sulfonamide 3 as a potent non-steroidal glucocorticoid receptor ligand. Further optimization of this lead generated indazoles 30 and 48 that were progressed to characterization in in vivo models. X-ray crystallography was used to gain further insight into the binding mode of selected ligands.

The discovery of potent and selective non-steroidal glucocorticoid receptor modulators, suitable for inhalation.,Edman K, Ahlgren R, Bengtsson M, Bladh H, Backstrom S, Dahmen J, Henriksson K, Hillertz P, Hulikal V, Jerre A, Kinchin L, Kase C, Lepisto M, Mile I, Nilsson S, Smailagic A, Taylor J, Tjornebo A, Wissler L, Hansson T Bioorg Med Chem Lett. 2014 Apr 2. pii: S0960-894X(14)00297-2. doi:, 10.1016/j.bmcl.2014.03.070. PMID:24755427^[7]

From MEDLINEÂ®/PubMedÂ®, a database of the U.S. National Library of Medicine.

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:https://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:https://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
↑ Edman K, Ahlgren R, Bengtsson M, Bladh H, Backstrom S, Dahmen J, Henriksson K, Hillertz P, Hulikal V, Jerre A, Kinchin L, Kase C, Lepisto M, Mile I, Nilsson S, Smailagic A, Taylor J, Tjornebo A, Wissler L, Hansson T. The discovery of potent and selective non-steroidal glucocorticoid receptor modulators, suitable for inhalation. Bioorg Med Chem Lett. 2014 Apr 2. pii: S0960-894X(14)00297-2. doi:, 10.1016/j.bmcl.2014.03.070. PMID:24755427 doi:https://dx.doi.org/10.1016/j.bmcl.2014.03.070

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OCA

[1] 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

[2] 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:https://dx.doi.org/10.1172/JCI115046

[3] 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:https://dx.doi.org/10.1172/JCI116410

[4] 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

[5] 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

[6] 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

[7] Edman K, Ahlgren R, Bengtsson M, Bladh H, Backstrom S, Dahmen J, Henriksson K, Hillertz P, Hulikal V, Jerre A, Kinchin L, Kase C, Lepisto M, Mile I, Nilsson S, Smailagic A, Taylor J, Tjornebo A, Wissler L, Hansson T. The discovery of potent and selective non-steroidal glucocorticoid receptor modulators, suitable for inhalation. Bioorg Med Chem Lett. 2014 Apr 2. pii: S0960-894X(14)00297-2. doi:, 10.1016/j.bmcl.2014.03.070. PMID:24755427 doi:https://dx.doi.org/10.1016/j.bmcl.2014.03.070

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@@ Line 2: / Line 2: @@
 <StructureSection load='4csj' size='340' side='right' caption='[[4csj]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4csj]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CSJ OCA]. <br>
+<table><tr><td colspan='2'>[[4csj]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4CSJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4CSJ FirstGlance]. <br>
 </td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NN7:N-[(2S)-1-[[1-(4-FLUOROPHENYL)INDAZOL-4-YL]AMINO]PROPAN-2-YL]-2,4,6-TRIMETHYL-BENZENESULFONAMIDE'>NN7</scene><br>
-<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Glucokinase Glucokinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.2 2.7.1.2] </span></td></tr>
 <tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4csj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4csj OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4csj RCSB], [http://www.ebi.ac.uk/pdbsum/4csj PDBsum]</span></td></tr>
 <table>

4csj: Difference between revisions

Revision as of 06:59, 21 May 2014

The discovery of potent selective glucocorticoid receptor modulators, suitable for inhalation

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

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