2ym5: Difference between revisions

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[[Image:2ym5.png|left|200px]]
==Crystal structure of checkpoint kinase 1 (Chk1) in complex with inhibitors==
<StructureSection load='2ym5' size='340' side='right' caption='[[2ym5]], [[Resolution|resolution]] 2.03&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2ym5]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2YM5 OCA]. <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=YM5:(3-{4-[(2S)-2-(AMINOMETHYL)MORPHOLIN-4-YL]-7H-PYRROLO[2,3-D]PYRIMIDIN-5-YL}PHENYL)METHANOL'>YM5</scene><br>
<tr><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2xf0|2xf0]], [[2brb|2brb]], [[2x8d|2x8d]], [[2wmr|2wmr]], [[2cgv|2cgv]], [[2brn|2brn]], [[2wmx|2wmx]], [[2ayp|2ayp]], [[2yer|2yer]], [[2cgu|2cgu]], [[1nvs|1nvs]], [[2ydj|2ydj]], [[2brm|2brm]], [[1nvq|1nvq]], [[2ydi|2ydi]], [[2wmt|2wmt]], [[2cgx|2cgx]], [[2bro|2bro]], [[2c3j|2c3j]], [[2wmw|2wmw]], [[2wmu|2wmu]], [[2x8e|2x8e]], [[2brh|2brh]], [[2c3k|2c3k]], [[1nvr|1nvr]], [[2wmq|2wmq]], [[2ym4|2ym4]], [[2cgw|2cgw]], [[1zlt|1zlt]], [[2yex|2yex]], [[2ym3|2ym3]], [[1zys|1zys]], [[2xez|2xez]], [[2br1|2br1]], [[1ia8|1ia8]], [[2ydk|2ydk]], [[2brg|2brg]], [[2wms|2wms]], [[2wmv|2wmv]], [[2c3l|2c3l]], [[2x8i|2x8i]], [[2xey|2xey]], [[2ym8|2ym8]], [[2ym7|2ym7]], [[2ym6|2ym6]]</td></tr>
<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=2ym5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ym5 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2ym5 RCSB], [http://www.ebi.ac.uk/pdbsum/2ym5 PDBsum]</span></td></tr>
<table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Pyrazolopyridine inhibitors with low micromolar potency for CHK1 and good selectivity against CHK2 were previously identified by fragment-based screening. The optimization of the pyrazolopyridines to a series of potent and CHK1-selective isoquinolines demonstrates how fragment-growing and scaffold morphing strategies arising from a structure-based understanding of CHK1 inhibitor binding can be combined to successfully progress fragment-derived hit matter to compounds with activity in vivo. The challenges of improving CHK1 potency and selectivity, addressing synthetic tractability, and achieving novelty in the crowded kinase inhibitor chemical space were tackled by multiple scaffold morphing steps, which progressed through tricyclic pyrimido[2,3-b]azaindoles to N-(pyrazin-2-yl)pyrimidin-4-amines and ultimately to imidazo[4,5-c]pyridines and isoquinolines. A potent and highly selective isoquinoline CHK1 inhibitor (SAR-020106) was identified, which potentiated the efficacies of irinotecan and gemcitabine in SW620 human colon carcinoma xenografts in nude mice.


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Structure-Guided Evolution of Potent and Selective CHK1 Inhibitors through Scaffold Morphing.,Reader JC, Matthews TP, Klair S, Cheung KM, Scanlon J, Proisy N, Addison G, Ellard J, Piton N, Taylor S, Cherry M, Fisher M, Boxall K, Burns S, Walton MI, Westwood IM, Hayes A, Eve P, Valenti M, de Haven Brandon A, Box G, van Montfort RL, Williams DH, Aherne GW, Raynaud FI, Eccles SA, Garrett MD, Collins I J Med Chem. 2011 Dec 22;54(24):8328-42. Epub 2011 Nov 23. PMID:22111927<ref>PMID:22111927</ref>
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{{STRUCTURE_2ym5|  PDB=2ym5  |  SCENE=  }}


===Crystal structure of checkpoint kinase 1 (Chk1) in complex with inhibitors===
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
 
</div>
 
== References ==
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==About this Structure==
[[2ym5]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2YM5 OCA].
 
==Reference==
<ref group="xtra">PMID:022111927</ref><ref group="xtra">PMID:019572549</ref><ref group="xtra">PMID:020561787</ref><references group="xtra"/>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Non-specific serine/threonine protein kinase]]
[[Category: Non-specific serine/threonine protein kinase]]

Revision as of 10:51, 14 May 2014

Crystal structure of checkpoint kinase 1 (Chk1) in complex with inhibitorsCrystal structure of checkpoint kinase 1 (Chk1) in complex with inhibitors

Structural highlights

2ym5 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.
Ligands:,
Related:2xf0, 2brb, 2x8d, 2wmr, 2cgv, 2brn, 2wmx, 2ayp, 2yer, 2cgu, 1nvs, 2ydj, 2brm, 1nvq, 2ydi, 2wmt, 2cgx, 2bro, 2c3j, 2wmw, 2wmu, 2x8e, 2brh, 2c3k, 1nvr, 2wmq, 2ym4, 2cgw, 1zlt, 2yex, 2ym3, 1zys, 2xez, 2br1, 1ia8, 2ydk, 2brg, 2wms, 2wmv, 2c3l, 2x8i, 2xey, 2ym8, 2ym7, 2ym6
Activity:Glucokinase, with EC number 2.7.1.2
Resources:FirstGlance, OCA, RCSB, PDBsum

Publication Abstract from PubMed

Pyrazolopyridine inhibitors with low micromolar potency for CHK1 and good selectivity against CHK2 were previously identified by fragment-based screening. The optimization of the pyrazolopyridines to a series of potent and CHK1-selective isoquinolines demonstrates how fragment-growing and scaffold morphing strategies arising from a structure-based understanding of CHK1 inhibitor binding can be combined to successfully progress fragment-derived hit matter to compounds with activity in vivo. The challenges of improving CHK1 potency and selectivity, addressing synthetic tractability, and achieving novelty in the crowded kinase inhibitor chemical space were tackled by multiple scaffold morphing steps, which progressed through tricyclic pyrimido[2,3-b]azaindoles to N-(pyrazin-2-yl)pyrimidin-4-amines and ultimately to imidazo[4,5-c]pyridines and isoquinolines. A potent and highly selective isoquinoline CHK1 inhibitor (SAR-020106) was identified, which potentiated the efficacies of irinotecan and gemcitabine in SW620 human colon carcinoma xenografts in nude mice.

Structure-Guided Evolution of Potent and Selective CHK1 Inhibitors through Scaffold Morphing.,Reader JC, Matthews TP, Klair S, Cheung KM, Scanlon J, Proisy N, Addison G, Ellard J, Piton N, Taylor S, Cherry M, Fisher M, Boxall K, Burns S, Walton MI, Westwood IM, Hayes A, Eve P, Valenti M, de Haven Brandon A, Box G, van Montfort RL, Williams DH, Aherne GW, Raynaud FI, Eccles SA, Garrett MD, Collins I J Med Chem. 2011 Dec 22;54(24):8328-42. Epub 2011 Nov 23. PMID:22111927[1]

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

References

  1. ↑ Reader JC, Matthews TP, Klair S, Cheung KM, Scanlon J, Proisy N, Addison G, Ellard J, Piton N, Taylor S, Cherry M, Fisher M, Boxall K, Burns S, Walton MI, Westwood IM, Hayes A, Eve P, Valenti M, de Haven Brandon A, Box G, van Montfort RL, Williams DH, Aherne GW, Raynaud FI, Eccles SA, Garrett MD, Collins I. Structure-Guided Evolution of Potent and Selective CHK1 Inhibitors through Scaffold Morphing. J Med Chem. 2011 Dec 22;54(24):8328-42. Epub 2011 Nov 23. PMID:22111927 doi:10.1021/jm2007326

2ym5, resolution 2.03Å

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