4FOC

Crystal structure of human anaplastic lymphoma kinase in complex with acyliminobenzimidazole inhibitor 2

4FOC の概要

• エントリーDOI: 10.2210/pdb4foc/pdb
• 関連するPDBエントリー: 4FNW 4FNX 4FNY 4FNZ 4FOB 4FOD
• 分子名称: ALK tyrosine kinase receptor, methyl cis-4-[2-(benzoylamino)-6-(piperidin-1-ylmethyl)-1H-benzimidazol-1-yl]cyclohexanecarboxylate (3 entities in total)
• 機能のキーワード: receptor tyrosine kinase, inhibitor, crizotinib, neuroblastoma, cd246, phosphotransferase, npm-alk, eml4-alk, in situ proteolysis, transferase-inhibitor complex, transferase/inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cell membrane; Single-pass type I membrane protein: Q9UM73
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 40530.57

構造登録者

Whittington, D.A.,Epstein, L.F.,Chen, H. (登録日: 2012-06-20, 公開日: 2012-07-11, 最終更新日: 2024-02-28)

主引用文献

Lewis, R.T.,Bode, C.M.,Choquette, D.M.,Potashman, M.,Romero, K.,Stellwagen, J.C.,Teffera, Y.,Moore, E.,Whittington, D.A.,Chen, H.,Epstein, L.F.,Emkey, R.,Andrews, P.S.,Yu, V.L.,Saffran, D.C.,Xu, M.,Drew, A.,Merkel, P.,Szilvassy, S.,Brake, R.L.
The Discovery and Optimization of a Novel Class of Potent, Selective, and Orally Bioavailable Anaplastic Lymphoma Kinase (ALK) Inhibitors with Potential Utility for the Treatment of Cancer.
J.Med.Chem., 55:6523-6540, 2012

PubMed Abstract: A class of 2-acyliminobenzimidazoles has been developed as potent and selective inhibitors of anaplastic lymphoma kinase (ALK). Structure based design facilitated the rapid development of structure-activity relationships (SAR) and the optimization of kinase selectivity. Introduction of an optimally placed polar substituent was key to solving issues of metabolic stability and led to the development of potent, selective, orally bioavailable ALK inhibitors. Compound 49 achieved substantial tumor regression in an NPM-ALK driven murine tumor xenograft model when dosed qd. Compounds 36 and 49 show favorable potency and PK characteristics in preclinical species indicative of suitability for further development.

PubMed: 22734674
DOI: 10.1021/jm3005866

実験手法

X-RAY DIFFRACTION (1.7 Å)