1uom: Difference between revisions
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==Overview== | ==Overview== | ||
As part of a program aimed at the development of selective estrogen, receptor modulators (SERMs), tetrahydroisoquinoline derivative 27 was, discovered by high throughput screening. Successive replacements of the, p-F substituent of 27 by an aminoethoxy side chain and of the 1-H of the, tetrahydroisoquinoline core by a 1-Me group provided analogues 19 and 20., These compounds showed potencies in a cell-based reporter gene assay (ERE, assay) varying between 0.6 and 20 nM and displayed antagonist behaviors in, the MCF-7 human breast adenocarcinoma cell line with IC(50)s in the range, of 2-36 nM. The effect of N-phenyl substituents on the activity and, pharmacokinetic properties of tetrahydroisoquinoline analogues was, explored. As a result of this investigation, two potent derivatives, . | As part of a program aimed at the development of selective estrogen, receptor modulators (SERMs), tetrahydroisoquinoline derivative 27 was, discovered by high throughput screening. Successive replacements of the, p-F substituent of 27 by an aminoethoxy side chain and of the 1-H of the, tetrahydroisoquinoline core by a 1-Me group provided analogues 19 and 20., These compounds showed potencies in a cell-based reporter gene assay (ERE, assay) varying between 0.6 and 20 nM and displayed antagonist behaviors in, the MCF-7 human breast adenocarcinoma cell line with IC(50)s in the range, of 2-36 nM. The effect of N-phenyl substituents on the activity and, pharmacokinetic properties of tetrahydroisoquinoline analogues was, explored. As a result of this investigation, two potent derivatives, bearing a p-F N-aryl group, 19c and 20c, were discovered as candidates, suitable for further profiling. To gain insight into the ligand-receptor, interaction, the X-ray crystallographic structure of the 1-H, tetrahydroisoquinoline derivative (R)-18a in complex with ERalpha-ligand, binding domain (LBD)(301)(-)(553)/C-->S triple mutant was solved to 2.28, A. An overlay of this X-ray crystal structure with that reported for the, complex of ERalpha-LBD(301)(-)(553)/carboxymethylated C and raloxifene (5), shows that both compounds bind to the same cleft of the receptor and, display comparable binding modes, with differences being observed in the, conformation of their "D-ring" phenyl groups. | ||
==About this Structure== | ==About this Structure== | ||
1UOM is a | 1UOM is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with PTI as [http://en.wikipedia.org/wiki/ligand ligand]. Structure known Active Site: PTI. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1UOM OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: zinc-finger]] | [[Category: zinc-finger]] | ||
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Revision as of 11:28, 5 November 2007
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THE STRUCTURE OF ESTROGEN RECEPTOR IN COMPLEX WITH A SELECTIVE AND POTENT TETRAHYDROISOCHIOLIN LIGAND.
Overview
As part of a program aimed at the development of selective estrogen, receptor modulators (SERMs), tetrahydroisoquinoline derivative 27 was, discovered by high throughput screening. Successive replacements of the, p-F substituent of 27 by an aminoethoxy side chain and of the 1-H of the, tetrahydroisoquinoline core by a 1-Me group provided analogues 19 and 20., These compounds showed potencies in a cell-based reporter gene assay (ERE, assay) varying between 0.6 and 20 nM and displayed antagonist behaviors in, the MCF-7 human breast adenocarcinoma cell line with IC(50)s in the range, of 2-36 nM. The effect of N-phenyl substituents on the activity and, pharmacokinetic properties of tetrahydroisoquinoline analogues was, explored. As a result of this investigation, two potent derivatives, bearing a p-F N-aryl group, 19c and 20c, were discovered as candidates, suitable for further profiling. To gain insight into the ligand-receptor, interaction, the X-ray crystallographic structure of the 1-H, tetrahydroisoquinoline derivative (R)-18a in complex with ERalpha-ligand, binding domain (LBD)(301)(-)(553)/C-->S triple mutant was solved to 2.28, A. An overlay of this X-ray crystal structure with that reported for the, complex of ERalpha-LBD(301)(-)(553)/carboxymethylated C and raloxifene (5), shows that both compounds bind to the same cleft of the receptor and, display comparable binding modes, with differences being observed in the, conformation of their "D-ring" phenyl groups.
About this Structure
1UOM is a Single protein structure of sequence from Homo sapiens with PTI as ligand. Structure known Active Site: PTI. Full crystallographic information is available from OCA.
Reference
Estrogen receptor modulators: identification and structure-activity relationships of potent ERalpha-selective tetrahydroisoquinoline ligands., Renaud J, Bischoff SF, Buhl T, Floersheim P, Fournier B, Halleux C, Kallen J, Keller H, Schlaeppi JM, Stark W, J Med Chem. 2003 Jul 3;46(14):2945-57. PMID:12825935
Page seeded by OCA on Mon Nov 5 13:33:26 2007
Proteopedia Page Contributors and Editors (what is this?)
- Pages with broken file links
- Homo sapiens
- Single protein
- Bischoff, S.F.
- Buhl, T.
- Fournier, B.
- Halleux, C.
- Kallen, J.
- Keller, H.
- Renaud, J.
- Stark, W.
- PTI
- Alternative splicing
- Dna-binding
- Nuclear protein
- Phosphorylation
- Polymorphism 3d-structure
- Receptor
- Selective estrogen receptor modulators
- Serm
- Steroid-binding
- Transcription regulation
- Zinc-finger
