4c4f: Difference between revisions
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4c4f]] is a 1 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=4C4F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4C4F FirstGlance]. <br> | <table><tr><td colspan='2'>[[4c4f]] is a 1 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=4C4F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4C4F FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7CE:N-(2-METHOXYPHENYL)-2-(1,3-OXAZOL-5-YL)-1H-PYRROLO[3,2-C]PYRIDIN-6-AMINE'>7CE</scene>, <scene name='pdbligand=7PE:2-(2-(2-(2-(2-(2-ETHOXYETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHANOL'>7PE</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</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]] 2.36Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7CE:N-(2-METHOXYPHENYL)-2-(1,3-OXAZOL-5-YL)-1H-PYRROLO[3,2-C]PYRIDIN-6-AMINE'>7CE</scene>, <scene name='pdbligand=7PE:2-(2-(2-(2-(2-(2-ETHOXYETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHOXY)ETHANOL'>7PE</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</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=4c4f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c4f OCA], [https://pdbe.org/4c4f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4c4f RCSB], [https://www.ebi.ac.uk/pdbsum/4c4f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4c4f ProSAT]</span></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=4c4f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c4f OCA], [https://pdbe.org/4c4f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4c4f RCSB], [https://www.ebi.ac.uk/pdbsum/4c4f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4c4f ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[https://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> | |||
<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. | |||
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> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4c4f" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
Latest revision as of 15:03, 20 December 2023
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
FunctionTTK_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.[1] Publication Abstract from PubMedThe 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[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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