2YM5

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

Summary for 2YM5

• Entry DOI: 10.2210/pdb2ym5/pdb
• Related: 1IA8 1NVQ 1NVR 1NVS 1ZLT 1ZYS 2AYP 2BR1 2BRB 2BRG 2BRH 2BRM 2BRN 2BRO 2C3J 2C3K 2C3L 2CGU 2CGV 2CGW 2CGX 2WMQ 2WMR 2WMS 2WMT 2WMU 2WMV 2WMW 2WMX 2X8D 2X8E 2X8I 2XEY 2XEZ 2XF0 2YDI 2YDJ 2YDK 2YER 2YEX 2YM3 2YM4 2YM6 2YM7 2YM8
• Descriptor: SERINE/THREONINE-PROTEIN KINASE CHK1, (3-{4-[(2S)-2-(AMINOMETHYL)MORPHOLIN-4-YL]-7H-PYRROLO[2,3-D]PYRIMIDIN-5-YL}PHENYL)METHANOL, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: transferase, dna repair
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Nucleus: O14757
• Total number of polymer chains: 1
• Total formula weight: 33444.45

Authors

Reader, J.C.,Matthews, T.P.,Klair, S.,Cheung, K.M.J.,Scanlon, J.,Proisy, N.,Addison, G.,Ellard, J.,Piton, N.,Taylor, S.,Cherry, M.,Fisher, M.,Boxall, K.,Burns, S.,Walton, M.I.,Westwood, I.M.,Hayes, A.,Eve, P.,Valenti, M.,Brandon, A.H.,Box, G.,vanMontfort, R.L.M.,Williams, D.H.,Aherne, G.W.,Raynaud, F.I.,Eccles, S.A.,Garrett, M.D.,Collins, I. (deposition date: 2011-06-06, release date: 2012-01-11, Last modification date: 2023-12-20)

Primary citation

Reader, J.C.,Matthews, T.P.,Klair, S.,Cheung, K.M.J.,Scanlon, J.,Proisy, N.,Addison, G.,Ellard, J.,Piton, N.,Taylor, S.,Cherry, M.,Fisher, M.,Boxall, K.,Burns, S.,Walton, M.I.,Westwood, I.M.,Hayes, A.,Eve, P.,Valenti, M.,De Haven Brandon, A.,Box, G.,Van Montfort, R.L.M.,Williams, D.H.,Aherne, G.W.,Raynaud, F.I.,Eccles, S.A.,Garrett, M.D.,Collins, I.
Structure-Guided Evolution of Potent and Selective Chk1 Inhibitors Through Scaffold Morphing.
J.Med.Chem., 54:8328-, 2011

PubMed Abstract: 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.

PubMed: 22111927
DOI: 10.1021/JM2007326

Experimental method

X-RAY DIFFRACTION (2.03 Å)