3QJZ

Crystal structure of PI3K-gamma in complex with benzothiazole 1

3QJZ の概要

• エントリーDOI: 10.2210/pdb3qjz/pdb
• 関連するPDBエントリー: 3QK0
• 分子名称: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, N-{6-[2-(methylsulfanyl)pyrimidin-4-yl]-1,3-benzothiazol-2-yl}acetamide, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: p110, transferase, kinase, inhibitor, atp-binding, p84, p101, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 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: 110236.52

構造登録者

Whittington, D.A.,Tang, J.,Yakowec, P. (登録日: 2011-01-31, 公開日: 2011-03-30, 最終更新日: 2023-09-13)

主引用文献

D'Angelo, N.D.,Kim, T.S.,Andrews, K.,Booker, S.K.,Caenepeel, S.,Chen, K.,D'Amico, D.,Freeman, D.,Jiang, J.,Liu, L.,McCarter, J.D.,San Miguel, T.,Mullady, E.L.,Schrag, M.,Subramanian, R.,Tang, J.,Wahl, R.C.,Wang, L.,Whittington, D.A.,Wu, T.,Xi, N.,Xu, Y.,Yakowec, P.,Yang, K.,Zalameda, L.P.,Zhang, N.,Hughes, P.,Norman, M.H.
Discovery and Optimization of a Series of Benzothiazole Phosphoinositide 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Dual Inhibitors.
J.Med.Chem., 54:1789-1811, 2011

PubMed Abstract: Phosphoinositide 3-kinase α (PI3Kα) is a lipid kinase that plays a key regulatory role in several cellular processes. The mutation or amplification of this kinase in humans has been implicated in the growth of multiple tumor types. Consequently, PI3Kα has become a target of intense research for drug discovery. Our studies began with the identification of benzothiazole compound 1 from a high throughput screen. Extensive SAR studies led to the discovery of sulfonamide 45 as an early lead, based on its in vitro cellular potency. Subsequent modifications of the central pyrimidine ring dramatically improved enzyme and cellular potency and led to the identification of chloropyridine 70. Further arylsulfonamide SAR studies optimized in vitro clearance and led to the identification of 82 as a potent dual inhibitor of PI3K and mTOR. This molecule exhibited potent enzyme and cell activity, low clearance, and high oral bioavailability. In addition, compound 82 demonstrated tumor growth inhibition in U-87 MG, A549, and HCT116 tumor xenograft models.

PubMed: 21332118
DOI: 10.1021/jm1014605

実験手法

X-RAY DIFFRACTION (2.9 Å)