4O2P

Kinase domain of cSrc in complex with a substituted pyrazolopyrimidine

4O2P の概要

• エントリーDOI: 10.2210/pdb4o2p/pdb
• 分子名称: Proto-oncogene tyrosine-protein kinase Src, 1-[(2R)-2-chloro-2-phenylethyl]-6-{[2-(morpholin-4-yl)ethyl]sulfanyl}-N-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (3 entities in total)
• 機能のキーワード: pyrazolo-pyrimidine ligand, type i, dfg-in, tyrosine protein kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Gallus gallus (bantam,chickens)
• 細胞内の位置: Cell membrane : P00523
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 66443.37

構造登録者

Richters, A.,Rauh, D. (登録日: 2013-12-17, 公開日: 2015-03-04, 最終更新日: 2023-09-20)

主引用文献

Tintori, C.,Fallacara, A.L.,Radi, M.,Zamperini, C.,Dreassi, E.,Crespan, E.,Maga, G.,Schenone, S.,Musumeci, F.,Brullo, C.,Richters, A.,Gasparrini, F.,Angelucci, A.,Festuccia, C.,Delle Monache, S.,Rauh, D.,Botta, M.
Combining X-ray Crystallography and Molecular Modeling toward the Optimization of Pyrazolo[3,4-d]pyrimidines as Potent c-Src Inhibitors Active in Vivo against Neuroblastoma.
J.Med.Chem., 58:347-361, 2015

PubMed Abstract: c-Src is a tyrosine kinase belonging to the Src-family kinases. It is overexpressed and/or hyperactivated in a variety of cancer cells, thus its inhibition has been predicted to have therapeutic effects in solid tumors. Recently, the pyrazolo[3,4-d]pyrimidine 3 was reported as a dual c-Src/Abl inhibitor. Herein we describe a multidisciplinary drug discovery approach for the optimization of the lead 3 against c-Src. Starting from the X-ray crystal structure of c-Src in complex with 3, Monte Carlo free energy perturbation calculations were applied to guide the design of c-Src inhibitors with improved activities. As a result, the introduction of a meta hydroxyl group on the C4 anilino ring was computed to be particularly favorable. The potency of the synthesized inhibitors was increased with respect to the starting lead 3. The best identified compounds were also found active in the inhibition of neuroblastoma cell proliferation. Furthermore, compound 29 also showed in vivo activity in xenograft model using SH-SY5Y cells.

PubMed: 25469771
DOI: 10.1021/jm5013159

実験手法

X-RAY DIFFRACTION (2.1 Å)