5eh0: Difference between revisions

Latest revision as of 06:26, 5 July 2023

Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle kinase 1 (MPS1) Using a Structure-Based Hydridization Approach

Structural highlights

5eh0 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.18Å
Ligands:	5NW, DMS
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.^[1]

Publication Abstract from PubMed

Monopolar spindle 1 (MPS1) plays a central role in the transition of cells from metaphase to anaphase and is one of the main components of the spindle assembly checkpoint. Chromosomally unstable cancer cells rely heavily on MPS1 to cope with the stress arising from abnormal numbers of chromosomes and centrosomes and are thus more sensitive to MPS1 inhibition than normal cells. We report the discovery and optimization of a series of new pyrido[3,4-d]pyrimidine based inhibitors via a structure-based hybridization approach from our previously reported inhibitor CCT251455 and a modestly potent screening hit. Compounds in this novel series display excellent potency and selectivity for MPS1, which translates into biomarker modulation in an in vivo human tumor xenograft model.

Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle Kinase 1 (MPS1) Using a Structure-Based Hybridization Approach.,Innocenti P, Woodward HL, Solanki S, Naud S, Westwood IM, Cronin N, Hayes A, Roberts J, Henley AT, Baker R, Faisal A, Mak GW, Box G, Valenti M, De Haven Brandon A, O'Fee L, Saville H, Schmitt J, Matijssen B, Burke R, van Montfort RL, Raynaud FI, Eccles SA, Linardopoulos S, Blagg J, Hoelder S J Med Chem. 2016 Apr 28;59(8):3671-88. doi: 10.1021/acs.jmedchem.5b01811. Epub, 2016 Apr 7. PMID:27055065^[2]

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

References

↑ Jelluma N, Brenkman AB, van den Broek NJ, Cruijsen CW, van Osch MH, Lens SM, Medema RH, Kops GJ. Mps1 phosphorylates Borealin to control Aurora B activity and chromosome alignment. Cell. 2008 Jan 25;132(2):233-46. doi: 10.1016/j.cell.2007.11.046. PMID:18243099 doi:10.1016/j.cell.2007.11.046
↑ Innocenti P, Woodward HL, Solanki S, Naud S, Westwood IM, Cronin N, Hayes A, Roberts J, Henley AT, Baker R, Faisal A, Mak GW, Box G, Valenti M, De Haven Brandon A, O'Fee L, Saville H, Schmitt J, Matijssen B, Burke R, van Montfort RL, Raynaud FI, Eccles SA, Linardopoulos S, Blagg J, Hoelder S. Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle Kinase 1 (MPS1) Using a Structure-Based Hybridization Approach. J Med Chem. 2016 Apr 28;59(8):3671-88. doi: 10.1021/acs.jmedchem.5b01811. Epub, 2016 Apr 7. PMID:27055065 doi:https://dx.doi.org/10.1021/acs.jmedchem.5b01811

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Jelluma N, Brenkman AB, van den Broek NJ, Cruijsen CW, van Osch MH, Lens SM, Medema RH, Kops GJ. Mps1 phosphorylates Borealin to control Aurora B activity and chromosome alignment. Cell. 2008 Jan 25;132(2):233-46. doi: 10.1016/j.cell.2007.11.046. PMID:18243099 doi:10.1016/j.cell.2007.11.046

[2] Innocenti P, Woodward HL, Solanki S, Naud S, Westwood IM, Cronin N, Hayes A, Roberts J, Henley AT, Baker R, Faisal A, Mak GW, Box G, Valenti M, De Haven Brandon A, O'Fee L, Saville H, Schmitt J, Matijssen B, Burke R, van Montfort RL, Raynaud FI, Eccles SA, Linardopoulos S, Blagg J, Hoelder S. Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle Kinase 1 (MPS1) Using a Structure-Based Hybridization Approach. J Med Chem. 2016 Apr 28;59(8):3671-88. doi: 10.1021/acs.jmedchem.5b01811. Epub, 2016 Apr 7. PMID:27055065 doi:https://dx.doi.org/10.1021/acs.jmedchem.5b01811

[1]

[2]

@@ Line 3: / Line 3: @@
 <StructureSection load='5eh0' size='340' side='right'caption='[[5eh0]], [[Resolution|resolution]] 2.18&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5eh0]] 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=5EH0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5EH0 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5eh0]] 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=5EH0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5EH0 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5NW:N2-(2-METHOXY-4-(1-METHYL-1H-PYRAZOL-4-YL)PHENYL)-N8-NEOPENTYLPYRIDO[3,4-D]PYRIMIDINE-2,8-DIAMINE'>5NW</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</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]] 2.18&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TTK, MPS1, MPS1L1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5NW:N2-(2-METHOXY-4-(1-METHYL-1H-PYRAZOL-4-YL)PHENYL)-N8-NEOPENTYLPYRIDO[3,4-D]PYRIMIDINE-2,8-DIAMINE'>5NW</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=5eh0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5eh0 OCA], [https://pdbe.org/5eh0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5eh0 RCSB], [https://www.ebi.ac.uk/pdbsum/5eh0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5eh0 ProSAT]</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=5eh0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5eh0 OCA], [http://pdbe.org/5eh0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5eh0 RCSB], [http://www.ebi.ac.uk/pdbsum/5eh0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5eh0 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[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>
+[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 ==
@@ Line 27: / Line 26: @@
 __TOC__
 </StructureSection>
-[[Category: Dual-specificity kinase]]
+[[Category: Homo sapiens]]
-[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Baker, R]]
+[[Category: Baker R]]
-[[Category: Blagg, J]]
+[[Category: Blagg J]]
-[[Category: Box, G]]
+[[Category: Box G]]
-[[Category: Brandon, A De Haven]]
+[[Category: Burke R]]
-[[Category: Burke, R]]
+[[Category: Cronin N]]
-[[Category: Cronin, N]]
+[[Category: De Haven Brandon A]]
-[[Category: Eccles, S A]]
+[[Category: Eccles SA]]
-[[Category: Faisal, A]]
+[[Category: Faisal A]]
-[[Category: Fee, L O]]
+[[Category: Hayes A]]
-[[Category: Hayes, A]]
+[[Category: Henley AT]]
-[[Category: Henley, A T]]
+[[Category: Hoelder S]]
-[[Category: Hoelder, S]]
+[[Category: Innocenti P]]
-[[Category: Innocenti, P]]
+[[Category: Linardopoulos S]]
-[[Category: Linardopoulos, S]]
+[[Category: Mak G]]
-[[Category: Mak, G]]
+[[Category: Naud N]]
-[[Category: Montfort, R L.M van]]
+[[Category: O'Fee L]]
-[[Category: Naud, N]]
+[[Category: Raymaud FI]]
-[[Category: Raymaud, F I]]
+[[Category: Roberts J]]
-[[Category: Roberts, J]]
+[[Category: Saville J]]
-[[Category: Saville, J]]
+[[Category: Schmitt J]]
-[[Category: Schmitt, J]]
+[[Category: Solanki S]]
-[[Category: Solanki, S]]
+[[Category: Valenti M]]
-[[Category: Valenti, M]]
+[[Category: Westwood IM]]
-[[Category: Westwood, I M]]
+[[Category: Woodward HL]]
-[[Category: Woodward, H L]]
+[[Category: Van Montfort RLM]]
-[[Category: Transferase]]

5eh0: Difference between revisions

Latest revision as of 06:26, 5 July 2023

Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle kinase 1 (MPS1) Using a Structure-Based Hydridization Approach

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Navigation menu

Page actions

Page actions

Personal tools

Navigation

Search

Tools