4c4h: Difference between revisions

From Proteopedia
Jump to navigation Jump to search
← Older editNewer edit →
No edit summary
No edit summary
Line 1: Line 1:
{{STRUCTURE_4c4h|  PDB=4c4h  |  SCENE=  }}
==Structure-based design of orally bioavailable pyrrolopyridine inhibitors of the mitotic kinase MPS1==
===Structure-based design of orally bioavailable pyrrolopyridine inhibitors of the mitotic kinase MPS1===
<StructureSection load='4c4h' size='340' side='right' caption='[[4c4h]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
{{ABSTRACT_PUBMED_24256217}}
== Structural highlights ==
<table><tr><td colspan='2'>[[4c4h]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4C4H OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4C4H FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7PE:2-(2-(2-(2-(2-(2-ETHOXYETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHANOL'>7PE</scene>, <scene name='pdbligand=7RO:TERT-BUTYL+6-((2-CHLORO-4-(DIMETHYLCARBAMOYL)PHENYL)AMINO)-2-(1-METHYL-1H-PYRAZOL-4-YL)-1H-PYRROLO[3,2-C]PYRIDINE-1-CARBOXYLATE'>7RO</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4c4e|4c4e]], [[4c4f|4c4f]], [[4c4g|4c4g]], [[4c4i|4c4i]], [[4c4j|4c4j]]</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Dual-specificity_kinase Dual-specificity kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.12.1 2.7.12.1] </span></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=4c4h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c4h OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4c4h RCSB], [http://www.ebi.ac.uk/pdbsum/4c4h PDBsum]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The protein kinase MPS1 is a crucial component of the spindle assembly checkpoint signal and is aberrantly overexpressed in many human cancers. MPS1 is one of the top 25 genes overexpressed in tumors with chromosomal instability and aneuploidy. PTEN-deficient breast tumor cells are particularly dependent upon MPS1 for their survival, making it a target of significant interest in oncology. We report the discovery and optimization of potent and selective MPS1 inhibitors based on the 1H-pyrrolo[3,2-c]pyridine scaffold, guided by structure-based design and cellular characterization of MPS1 inhibition, leading to 65 (CCT251455). This potent and selective chemical tool stabilizes an inactive conformation of MPS1 with the activation loop ordered in a manner incompatible with ATP and substrate-peptide binding; it displays a favorable oral pharmacokinetic profile, shows dose-dependent inhibition of MPS1 in an HCT116 human tumor xenograft model, and is an attractive tool compound to elucidate further the therapeutic potential of MPS1 inhibition.


==Function==
Structure-Based Design of Orally Bioavailable 1H-Pyrrolo[3,2-c]pyridine Inhibitors of Mitotic Kinase Monopolar Spindle 1 (MPS1).,Naud S, Westwood IM, Faisal A, Sheldrake P, Bavetsias V, Atrash B, Cheung KM, Liu M, Hayes A, Schmitt J, Wood A, Choi V, Boxall K, Mak G, Gurden M, Valenti M, de Haven Brandon A, Henley A, Baker R, McAndrew C, Matijssen B, Burke R, Hoelder S, Eccles SA, Raynaud FI, Linardopoulos S, van Montfort RL, Blagg J J Med Chem. 2013 Dec 2. PMID:24256217<ref>PMID:24256217</ref>
[[http://www.uniprot.org/uniprot/TTK_HUMAN TTK_HUMAN]] Phosphorylates proteins on serine, threonine, and tyrosine. Probably associated with cell proliferation. Essential for chromosome alignment by enhancing AURKB activity (via direct CDCA8 phosphorylation) at the centromere, and for the mitotic checkpoint.<ref>PMID:18243099</ref>


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[4c4h]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4C4H OCA].
</div>


==Reference==
==See Also==
<ref group="xtra">PMID:024256217</ref><references group="xtra"/><references/>
*[[Dual specificity protein kinase|Dual specificity protein kinase]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Dual-specificity kinase]]
[[Category: Dual-specificity kinase]]
[[Category: Human]]
[[Category: Human]]
[[Category: Atrash, B.]]
[[Category: Atrash, B]]
[[Category: Baker, R.]]
[[Category: Baker, R]]
[[Category: Bavetsias, V.]]
[[Category: Bavetsias, V]]
[[Category: Blagg, J.]]
[[Category: Blagg, J]]
[[Category: Boxall, K.]]
[[Category: Boxall, K]]
[[Category: Brandon, A de Haven.]]
[[Category: Brandon, A de Haven]]
[[Category: Burke, R.]]
[[Category: Burke, R]]
[[Category: Choi, V.]]
[[Category: Choi, V]]
[[Category: Eccles, S A.]]
[[Category: Eccles, S A]]
[[Category: Faisal, A.]]
[[Category: Faisal, A]]
[[Category: Gurden, M.]]
[[Category: Gurden, M]]
[[Category: Hayes, A.]]
[[Category: Hayes, A]]
[[Category: Henley, A.]]
[[Category: Henley, A]]
[[Category: Linardopoulos, S.]]
[[Category: Linardopoulos, S]]
[[Category: Liu, M.]]
[[Category: Liu, M]]
[[Category: Mak, G.]]
[[Category: Mak, G]]
[[Category: Matijssen, B.]]
[[Category: Matijssen, B]]
[[Category: McAndrew, C.]]
[[Category: McAndrew, C]]
[[Category: Montfort, R van.]]
[[Category: Montfort, R van]]
[[Category: Naud, S.]]
[[Category: Naud, S]]
[[Category: Raynaud, F I.]]
[[Category: Raynaud, F I]]
[[Category: Schmitt, J.]]
[[Category: Schmitt, J]]
[[Category: Sheldrake, P.]]
[[Category: Sheldrake, P]]
[[Category: Valenti, M.]]
[[Category: Valenti, M]]
[[Category: Westwood, I M.]]
[[Category: Westwood, I M]]
[[Category: Wood, A.]]
[[Category: Wood, A]]
[[Category: Mitosis]]
[[Category: Mitosis]]
[[Category: Protein kinase]]
[[Category: Protein kinase]]
[[Category: Structure-based design]]
[[Category: Structure-based design]]
[[Category: Transferase]]
[[Category: Transferase]]

Revision as of 21:00, 21 December 2014

Structure-based design of orally bioavailable pyrrolopyridine inhibitors of the mitotic kinase MPS1Structure-based design of orally bioavailable pyrrolopyridine inhibitors of the mitotic kinase MPS1

Structural highlights

4c4h is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:,
Activity:Dual-specificity kinase, with EC number 2.7.12.1
Resources:FirstGlance, OCA, RCSB, PDBsum

Publication Abstract from PubMed

The protein kinase MPS1 is a crucial component of the spindle assembly checkpoint signal and is aberrantly overexpressed in many human cancers. MPS1 is one of the top 25 genes overexpressed in tumors with chromosomal instability and aneuploidy. PTEN-deficient breast tumor cells are particularly dependent upon MPS1 for their survival, making it a target of significant interest in oncology. We report the discovery and optimization of potent and selective MPS1 inhibitors based on the 1H-pyrrolo[3,2-c]pyridine scaffold, guided by structure-based design and cellular characterization of MPS1 inhibition, leading to 65 (CCT251455). This potent and selective chemical tool stabilizes an inactive conformation of MPS1 with the activation loop ordered in a manner incompatible with ATP and substrate-peptide binding; it displays a favorable oral pharmacokinetic profile, shows dose-dependent inhibition of MPS1 in an HCT116 human tumor xenograft model, and is an attractive tool compound to elucidate further the therapeutic potential of MPS1 inhibition.

Structure-Based Design of Orally Bioavailable 1H-Pyrrolo[3,2-c]pyridine Inhibitors of Mitotic Kinase Monopolar Spindle 1 (MPS1).,Naud S, Westwood IM, Faisal A, Sheldrake P, Bavetsias V, Atrash B, Cheung KM, Liu M, Hayes A, Schmitt J, Wood A, Choi V, Boxall K, Mak G, Gurden M, Valenti M, de Haven Brandon A, Henley A, Baker R, McAndrew C, Matijssen B, Burke R, Hoelder S, Eccles SA, Raynaud FI, Linardopoulos S, van Montfort RL, Blagg J J Med Chem. 2013 Dec 2. PMID:24256217[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Naud S, Westwood IM, Faisal A, Sheldrake P, Bavetsias V, Atrash B, Cheung KM, Liu M, Hayes A, Schmitt J, Wood A, Choi V, Boxall K, Mak G, Gurden M, Valenti M, de Haven Brandon A, Henley A, Baker R, McAndrew C, Matijssen B, Burke R, Hoelder S, Eccles SA, Raynaud FI, Linardopoulos S, van Montfort RL, Blagg J. Structure-Based Design of Orally Bioavailable 1H-Pyrrolo[3,2-c]pyridine Inhibitors of Mitotic Kinase Monopolar Spindle 1 (MPS1). J Med Chem. 2013 Dec 2. PMID:24256217 doi:http://dx.doi.org/10.1021/jm401395s

4c4h, resolution 2.80Å

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA
Retrieved from "https://proteopedia.openfox.io/wiki/index.php?title=4c4h&oldid=2150487"