2ym3

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

Structural highlights 2ym3 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, 2yer, 2ayp, 2cgu, 1nvs, 2brm, 2ydj, 1nvq, 2ydi, 2wmt, 2cgx, 2c3j, 2bro, 2wmw, 2wmu, 2brh, 2x8e, 2c3k, 1nvr, 2wmq, 1zlt, 2cgw, 2yex, 2xez, 1zys, 1ia8, 2br1, 2brg, 2ydk, 2wmv, 2wms, 2x8i, 2c3l, 2xey, 2ym8, 2ym5, 2ym4, 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

spinqualitylabelsall models 2ym3, resolution 2.01Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image