3O50

Crystal structure of benzamide 9 bound to AuroraA

3O50 の概要

• エントリーDOI: 10.2210/pdb3o50/pdb
• 関連するPDBエントリー: 3O51
• 分子名称: cDNA FLJ58295, highly similar to Serine/threonine-protein kinase 6, N-{3-methyl-4-[(3-pyrimidin-4-ylpyridin-2-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (3 entities in total)
• 機能のキーワード: auroraa, kinase domain, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 62974.22

構造登録者

Huang, X. (登録日: 2010-07-27, 公開日: 2010-08-18, 最終更新日: 2024-02-21)

主引用文献

Cee, V.J.,Schenkel, L.B.,Hodous, B.L.,Deak, H.L.,Nguyen, H.N.,Olivieri, P.R.,Romero, K.,Bak, A.,Be, X.,Bellon, S.,Bush, T.L.,Cheng, A.C.,Chung, G.,Coats, S.,Eden, P.M.,Hanestad, K.,Gallant, P.L.,Gu, Y.,Huang, X.,Kendall, R.L.,Lin, M.H.,Morrison, M.J.,Patel, V.F.,Radinsky, R.,Rose, P.E.,Ross, S.,Sun, J.R.,Tang, J.,Zhao, H.,Payton, M.,Geuns-Meyer, S.D.
Discovery of a potent, selective, and orally bioavailable pyridinyl-pyrimidine phthalazine aurora kinase inhibitor.
J.Med.Chem., 53:6368-6377, 2010

PubMed Abstract: The discovery of aurora kinases as essential regulators of cell division has led to intense interest in identifying small molecule aurora kinase inhibitors for the potential treatment of cancer. A high-throughput screening effort identified pyridinyl-pyrimidine 6a as a moderately potent dual inhibitor of aurora kinases -A and -B. Optimization of this hit resulted in an anthranilamide lead (6j) that possessed improved enzyme and cellular activity and exhibited a high level of kinase selectivity. However, this anthranilamide and subsequent analogues suffered from a lack of oral bioavailability. Converting the internally hydrogen-bonded six-membered pseudo-ring of the anthranilamide to a phthalazine (8a-b) led to a dramatic improvement in oral bioavailability (38-61%F) while maintaining the potency and selectivity characteristics of the anthranilamide series. In a COLO 205 tumor pharmacodynamic assay measuring phosphorylation of the aurora-B substrate histone H3 at serine 10 (p-histone H3), oral administration of 8b at 50 mg/kg demonstrated significant reduction in tumor p-histone H3 for at least 6 h.

PubMed: 20684549
DOI: 10.1021/jm100394y

実験手法

X-RAY DIFFRACTION (2 Å)