4OBQ

MAP4K4 in complex with inhibitor (compound 31), N-[3-(4-AMINOQUINAZOLIN-6-YL)-5-FLUOROPHENYL]-2-(PYRROLIDIN-1-YL)ACETAMIDE

4OBQ の概要

• エントリーDOI: 10.2210/pdb4obq/pdb
• 関連するPDBエントリー: 4OBO 4OBP
• 分子名称: Mitogen-activated protein kinase kinase kinase kinase 4, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: O95819
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 76325.10

構造登録者

Harris, S.F.,Wu, P.,Coons, M. (登録日: 2014-01-07, 公開日: 2014-04-23, 最終更新日: 2024-02-28)

主引用文献

Crawford, T.D.,Ndubaku, C.O.,Chen, H.,Boggs, J.W.,Bravo, B.J.,Delatorre, K.,Giannetti, A.M.,Gould, S.E.,Harris, S.F.,Magnuson, S.R.,McNamara, E.,Murray, L.J.,Nonomiya, J.,Sambrone, A.,Schmidt, S.,Smyczek, T.,Stanley, M.,Vitorino, P.,Wang, L.,West, K.,Wu, P.,Ye, W.
Discovery of Selective 4-Amino-pyridopyrimidine Inhibitors of MAP4K4 Using Fragment-Based Lead Identification and Optimization.
J.Med.Chem., 57:3484-3493, 2014

PubMed Abstract: Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) is a serine/threonine kinase implicated in the regulation of many biological processes. A fragment-based lead discovery approach was used to generate potent and selective MAP4K4 inhibitors. The fragment hit pursued in this article had excellent ligand efficiency (LE), an important attribute for subsequent successful optimization into drug-like lead compounds. The optimization efforts eventually led us to focus on the pyridopyrimidine series, from which 6-(2-fluoropyridin-4-yl)pyrido[3,2-d]pyrimidin-4-amine (29) was identified. This compound had low nanomolar potency, excellent kinase selectivity, and good in vivo exposure, and demonstrated in vivo pharmacodynamic effects in a human tumor xenograft model.

PubMed: 24673130
DOI: 10.1021/jm500155b

実験手法

X-RAY DIFFRACTION (2.19 Å)