5DEY

Crystal structure of PAK1 in complex with an inhibitor compound G-5555

5DEY の概要

• エントリーDOI: 10.2210/pdb5dey/pdb
• 関連するPDBエントリー: 5DEW 5DFP
• 分子名称: Serine/threonine-protein kinase PAK 1, 8-[(trans-5-amino-1,3-dioxan-2-yl)methyl]-6-[2-chloro-4-(6-methylpyridin-2-yl)phenyl]-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (3 entities in total)
• 機能のキーワード: transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm : Q13153
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 67558.45

構造登録者

Oh, A.,Tam, C.,Wang, W. (登録日: 2015-08-26, 公開日: 2016-01-27, 最終更新日: 2024-10-16)

主引用文献

Ndubaku, C.O.,Crawford, J.J.,Drobnick, J.,Aliagas, I.,Campbell, D.,Dong, P.,Dornan, L.M.,Duron, S.,Epler, J.,Gazzard, L.,Heise, C.E.,Hoeflich, K.P.,Jakubiak, D.,La, H.,Lee, W.,Lin, B.,Lyssikatos, J.P.,Maksimoska, J.,Marmorstein, R.,Murray, L.J.,O'Brien, T.,Oh, A.,Ramaswamy, S.,Wang, W.,Zhao, X.,Zhong, Y.,Blackwood, E.,Rudolph, J.
Design of Selective PAK1 Inhibitor G-5555: Improving Properties by Employing an Unorthodox Low-pK a Polar Moiety.
Acs Med.Chem.Lett., 6:1241-1246, 2015

PubMed Abstract: Signaling pathways intersecting with the p21-activated kinases (PAKs) play important roles in tumorigenesis and cancer progression. By recognizing that the limitations of FRAX1036 (1) were chiefly associated with the highly basic amine it contained, we devised a mitigation strategy to address several issues such as hERG activity. The 5-amino-1,3-dioxanyl moiety was identified as an effective means of reducing pK a and logP simultaneously. When positioned properly within the scaffold, this group conferred several benefits including potency, pharmacokinetics, and selectivity. Mouse xenograft PK/PD studies were carried out using an advanced compound, G-5555 (12), derived from this approach. These studies concluded that dose-dependent pathway modulation was achievable and paves the way for further in vivo investigations of PAK1 function in cancer and other diseases.

PubMed: 26713112
DOI: 10.1021/acsmedchemlett.5b00398

実験手法

X-RAY DIFFRACTION (2.1 Å)