2XM8

Co-crystal structure of a small molecule inhibitor bound to the kinase domain of Chk2

2XM8 の概要

• エントリーDOI: 10.2210/pdb2xm8/pdb
• 関連するPDBエントリー: 1GXC 2CN5 2CN8 2W0J 2W7X 2WTC 2WTD 2WTI 2WTJ 2XBJ 2XM9
• 分子名称: SERINE/THREONINE-PROTEIN KINASE CHK2, 2-{4-[(3S)-PYRROLIDIN-3-YLAMINO]QUINAZOLIN-2-YL}PHENOL (3 entities in total)
• 機能のキーワード: transferase, cancer
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Isoform 2: Nucleus. Isoform 4: Nucleus. Isoform 7: Nucleus. Isoform 9: Nucleus. Isoform 12: Nucleus. Nucleus, PML body: O96017
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 37418.21

構造登録者

Caldwell, J.J.,Welsh, E.J.,Matijssen, C.,Anderson, V.E.,Antoni, L.,Boxall, K.,Urban, F.,Hayes, A.,Raynaud, F.I.,Rigoreau, L.J.,Raynham, T.,Aherne, G.W.,Pearl, L.H.,Oliver, A.W.,Garrett, M.D.,Collins, I. (登録日: 2010-07-26, 公開日: 2011-01-12, 最終更新日: 2023-12-20)

主引用文献

Caldwell, J.J.,Welsh, E.J.,Matijssen, C.,Anderson, V.E.,Antoni, L.,Boxall, K.,Urban, F.,Hayes, A.,Raynaud, F.I.,Rigoreau, L.J.,Raynham, T.,Aherne, G.W.,Pearl, L.H.,Oliver, A.W.,Garrett, M.D.,Collins, I.
Structure-Based Design of Potent and Selective 2-(Quinazolin-2-Yl)Phenol Inhibitors of Checkpoint Kinase 2.
J.Med.Chem., 54:580-, 2011

PubMed Abstract: Structure-based design was applied to the optimization of a series of 2-(quinazolin-2-yl)phenols to generate potent and selective ATP-competitive inhibitors of the DNA damage response signaling enzyme checkpoint kinase 2 (CHK2). Structure-activity relationships for multiple substituent positions were optimized separately and in combination leading to the 2-(quinazolin-2-yl)phenol 46 (IC(50) 3 nM) with good selectivity for CHK2 against CHK1 and a wider panel of kinases and with promising in vitro ADMET properties. Off-target activity at hERG ion channels shown by the core scaffold was successfully reduced by the addition of peripheral polar substitution. In addition to showing mechanistic inhibition of CHK2 in HT29 human colon cancer cells, a concentration dependent radioprotective effect in mouse thymocytes was demonstrated for the potent inhibitor 46 (CCT241533).

PubMed: 21186793
DOI: 10.1021/JM101150B

実験手法

X-RAY DIFFRACTION (3.4 Å)