6N6O

Crystal structure of the human TTK in complex with an inhibitor

6N6O の概要

• エントリーDOI: 10.2210/pdb6n6o/pdb
• 関連するPDBエントリー: 6B4W
• 分子名称: Dual specificity protein kinase TTK, 4-({5-chloro-4-[(cis-4-hydroxy-4-methylcyclohexyl)oxy]-7H-pyrrolo[2,3-d]pyrimidin-2-yl}amino)-N,N-dimethyl-3-{[(2R)-1,1,1-trifluoropropan-2-yl]oxy}benzamide, PENTAETHYLENE GLYCOL, ... (5 entities in total)
• 機能のキーワード: protein kinase activity protein serine/threonine/tyrosine kinase activity atp binding protein phosphorylation mitotic cell cycle checkpoint chromosome separation, signaling protein
• 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: 33783.12

構造登録者

Fenalti, G. (登録日: 2018-11-26, 公開日: 2019-05-15, 最終更新日: 2024-10-30)

主引用文献

Riggs, J.R.,Elsner, J.,Cashion, D.,Robinson, D.,Tehrani, L.,Nagy, M.,Fultz, K.E.,Krishna Narla, R.,Peng, X.,Tran, T.,Kulkarni, A.,Bahmanyar, S.,Condroski, K.,Pagarigan, B.,Fenalti, G.,LeBrun, L.,Leftheris, K.,Zhu, D.,Boylan, J.F.
Design and Optimization Leading to an Orally Active TTK Protein Kinase Inhibitor with Robust Single Agent Efficacy.
J.Med.Chem., 62:4401-4410, 2019

PubMed Abstract: Triple negative breast cancer (TNBC) is an aggressive disease with high relapse rates and few treatment options. Outlined in previous publications, we identified a series of potent, dual TTK/CLK2 inhibitors with strong efficacy in TNBC xenograft models. Pharmacokinetic properties and kinome selectivity were optimized, resulting in the identification of a new series of potent, selective, and orally bioavailable TTK inhibitors. We describe here the structure-activity relationship of the 2,4-disubstituted-7 H-pyrrolo[2,3- d]pyrimidine series, leading to significant single agent efficacy in a TNBC xenograft model without body weight loss. The design effort evolving an iv-dosed TTK/CLK2 inhibitor to an orally bioavailable TTK inhibitor is described.

PubMed: 30998356
DOI: 10.1021/acs.jmedchem.8b01869

実験手法

X-RAY DIFFRACTION (2.6 Å)