2YDI

Discovery of Checkpoint Kinase Inhibitor AZD7762 by Structure Based Design and Optimization of Thiophene Carboxamide Ureas

2YDI の概要

• エントリーDOI: 10.2210/pdb2ydi/pdb
• 関連するPDBエントリー: 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 2YDJ 2YDK
• 分子名称: SERINE/THREONINE-PROTEIN KINASE CHK1, SULFATE ION, 5-[4-(2-DIMETHYLAMINOETHYLOXY)PHENYL]-2-UREIDO-THIOPHENE-3-CARBOXAMIDE, ... (4 entities in total)
• 機能のキーワード: transferase, chk
• 由来する生物種: HOMO SAPIENS (HUMAN)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 33487.47

構造登録者

Read, J.A.,Breed, J.,Haye, H.,McCall, E.,Rowsell, S.,Vallentine, A.,White, A. (登録日: 2011-03-21, 公開日: 2012-04-04, 最終更新日: 2024-05-08)

主引用文献

Oza, V.,Ashwell, S.,Almeida, L.,Brassil, P.,Breed, J.,Deng, C.,Gero, T.,Grondine, M.,Horn, C.,Ioannidis, S.,Liu, D.,Lyne, P.,Newcombe, N.,Pass, M.,Read, J.A.,Ready, S.,Rowsell, S.,Su, M.,Toader, D.,Vasbinder, M.,Yu, D.,Yu, Y.,Xue, Y.,Zabludoff, S.,Janetka, J.
Discovery of Checkpoint Kinase Inhibitor (S)-5-(3-Fluorophenyl)-N-(Piperidin-3-Yl)-3-Ureidothiophene-2-Carboxamide (Azd7762) by Structure-Based Design and Optimization of Thiophenecarboxamide Ureas.
J.Med.Chem., 55:5130-, 2012

PubMed Abstract: Checkpoint kinases CHK1 and CHK2 are activated in response to DNA damage that results in cell cycle arrest, allowing sufficient time for DNA repair. Agents that lead to abrogation of such checkpoints have potential to increase the efficacy of such compounds as chemo- and radiotherapies. Thiophenecarboxamide ureas (TCUs) were identified as inhibitors of CHK1 by high throughput screening. A structure-based approach is described using crystal structures of JNK1 and CHK1 in complex with 1 and 2 and of the CHK1-3b complex. The ribose binding pocket of CHK1 was targeted to generate inhibitors with excellent cellular potency and selectivity over CDK1and IKKβ, key features lacking from the initial compounds. Optimization of 3b resulted in the identification of a regioisomeric 3-TCU lead 12a. Optimization of 12a led to the discovery of the clinical candidate 4 (AZD7762), which strongly potentiates the efficacy of a variety of DNA-damaging agents in preclinical models.

PubMed: 22551018
DOI: 10.1021/JM300025R

実験手法

X-RAY DIFFRACTION (1.6 Å)