4ANX

Complexes of PI3Kgamma with isoform selective inhibitors.

4ANX の概要

• エントリーDOI: 10.2210/pdb4anx/pdb
• 関連するPDBエントリー: 1E8Y 1E8Z 1HE8 2A4Z 2A5U 2CHW 2CHX 2CHZ 2V4L 3ZVV 3ZW3 4ANU 4ANV 4ANW
• 分子名称: PHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT GAMMA ISOFORM, 5-{3-[(4-{3-[4-(1-methylethyl)phenyl]pyrazin-2-yl}piperazin-1-yl)sulfonyl]phenyl}pyrimidin-2-amine (3 entities in total)
• 機能のキーワード: transferase
• 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: 112615.25

構造登録者

Foster, P.G.,Lougheed, J.C. (登録日: 2012-03-22, 公開日: 2012-05-09, 最終更新日: 2024-05-01)

主引用文献

Leahy, J.W.,Buhr, C.A.,Johnson, H.W.B.,Kim, B.G.,Baik, T.,Cannoy, J.,Forsyth, T.P.,Jeong, J.W.,Lee, M.S.,Ma, S.,Noson, K.,Wang, L.,Williams, M.,Nuss, J.M.,Brooks, E.,Heald, N.,Holst, C.,Jaeger, C.,Lam, S.,Lougheed, J.C.,Nguyen, L.,Plonowski, A.,Stout, T.,Foster, P.G.,Wu, X.,Yakes, M.F.,Yu, R.,Zhang, W.,Lamb, P.,Raeber, O.
The Discovery of a Novel Series of Potent and Orally Bioavailable Phosphoinositide 3-Kinase Gamma Inhibitors
J.Med.Chem., 55:5467-, 2012

PubMed Abstract: The phosphoinositide 3-kinases (PI3Ks) have been linked to an extraordinarily diversified group of cellular functions making these enzymes compelling targets for the treatment of disease. A large body of evidence has linked PI3Kγ to the modulation of autoimmune and inflammatory processes making it an intriguing target for drug discovery. Our high-throughput screening (HTS) campaign revealed two hits that were nominated for further optimization studies. The in vitro activity of the first HTS hit, designated as the sulfonylpiperazine scaffold, was optimized utilizing structure-based design. However, nonoptimal pharmacokinetic properties precluded this series from further studies. An overlay of the X-ray structures of the sulfonylpiperazine scaffold and the second HTS hit within their complexes with PI3Kγ revealed a high degree of overlap. This feature was utilized to design a series of hybrid analogues including advanced leads such as 31 with desirable potency, selectivity, and oral bioavailability.

PubMed: 22548342
DOI: 10.1021/JM300403A

実験手法

X-RAY DIFFRACTION (2.73 Å)