6GGN

In vitro and in vivo characterization of a novel, highly potent p53-MDM2 inhibitor

6GGN の概要

• エントリーDOI: 10.2210/pdb6ggn/pdb
• 分子名称: E3 ubiquitin-protein ligase Mdm2, (4~{S})-4-(4-chloranyl-2-methyl-phenyl)-5-(5-chloranyl-2-methyl-phenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-3-propan-2-yl-4~{H}-pyrrolo[3,4-d]imidazol-6-one, CHLORIDE ION, ... (4 entities in total)
• 機能のキーワード: ppi with p53, inhibitor complex, cell cycle
• 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: 11743.96

構造登録者

Kallen, J. (登録日: 2018-05-03, 公開日: 2018-09-26, 最終更新日: 2024-01-17)

主引用文献

Vaupel, A.,Holzer, P.,Ferretti, S.,Guagnano, V.,Kallen, J.,Mah, R.,Masuya, K.,Ruetz, S.,Rynn, C.,Schlapbach, A.,Stachyra, T.,Stutz, S.,Todorov, M.,Jeay, S.,Furet, P.
In vitro and in vivo characterization of a novel, highly potent p53-MDM2 inhibitor.
Bioorg. Med. Chem. Lett., 28:3404-3408, 2018

PubMed Abstract: Small molecule inhibitors of the p53-MDM2 protein complex are under intense investigation in clinical trials as anti-cancer agents, including our first generation inhibitor NVP-CGM097. We recently described the rational design of a novel pyrazolopyrrolidinone core as a new lead structure and now we report on the synthesis and optimization of this to provide a highly potent lead compound. This new compound displayed excellent oral efficacy in our preclinical mechanistic in vivo model and marked a significant milestone towards the identification of our second generation clinical candidate NVP-HDM201.

PubMed: 30217415
DOI: 10.1016/j.bmcl.2018.08.027

実験手法

X-RAY DIFFRACTION (2 Å)