5IME

Crystal structure of P21-activated kinase 1 (PAK1) in complex with compound 9

5IME の概要

• エントリーDOI: 10.2210/pdb5ime/pdb
• 分子名称: Serine/threonine-protein kinase PAK 1, 8-(3-aminopropyl)-6-[2-chloro-4-(3-methyl-2-oxopyrazin-1(2H)-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: 67992.83

構造登録者

Li, D.,Wang, W. (登録日: 2016-03-06, 公開日: 2016-05-25, 最終更新日: 2023-09-27)

主引用文献

Rudolph, J.,Murray, L.J.,Ndubaku, C.O.,O'Brien, T.,Blackwood, E.,Wang, W.,Aliagas, I.,Gazzard, L.,Crawford, J.J.,Drobnick, J.,Lee, W.,Zhao, X.,Hoeflich, K.P.,Favor, D.A.,Dong, P.,Zhang, H.,Heise, C.E.,Oh, A.,Ong, C.C.,La, H.,Chakravarty, P.,Chan, C.,Jakubiak, D.,Epler, J.,Ramaswamy, S.,Vega, R.,Cain, G.,Diaz, D.,Zhong, Y.
Chemically Diverse Group I p21-Activated Kinase (PAK) Inhibitors Impart Acute Cardiovascular Toxicity with a Narrow Therapeutic Window.
J.Med.Chem., 59:5520-5541, 2016

PubMed Abstract: p21-activated kinase 1 (PAK1) has an important role in transducing signals in several oncogenic pathways. The concept of inhibiting this kinase has garnered significant interest over the past decade, particularly for targeting cancers associated with PAK1 amplification. Animal studies with the selective group I PAK (pan-PAK1, 2, 3) inhibitor G-5555 from the pyrido[2,3-d]pyrimidin-7-one class uncovered acute toxicity with a narrow therapeutic window. To attempt mitigating the toxicity, we introduced significant structural changes, culminating in the discovery of the potent pyridone side chain analogue G-9791. Mouse tolerability studies with this compound, other members of this series, and compounds from two structurally distinct classes revealed persistent toxicity and a correlation of minimum toxic concentrations and PAK1/2 mediated cellular potencies. Broad screening of selected PAK inhibitors revealed PAK1, 2, and 3 as the only overlapping targets. Our data suggest acute cardiovascular toxicity resulting from the inhibition of PAK2, which may be enhanced by PAK1 inhibition, and cautions against continued pursuit of pan-group I PAK inhibitors in drug discovery.

PubMed: 27167326
DOI: 10.1021/acs.jmedchem.6b00638

実験手法

X-RAY DIFFRACTION (2.217 Å)