1Z5M

Crystal Structure Of N1-[3-[[5-bromo-2-[[3-[(1-pyrrolidinylcarbonyl)amino]phenyl]amino]-4-pyrimidinyl]amino]propyl]-2,2-dimethylpropanediamide Complexed with Human PDK1

1Z5M の概要

• エントリーDOI: 10.2210/pdb1z5m/pdb
• 関連するPDBエントリー: 1h1w 1uu7 1uu8 1uu9 1uvr
• 分子名称: 3-phosphoinositide dependent protein kinase-1, SULFATE ION, CHLORIDE ION, ... (6 entities in total)
• 機能のキーワード: protein inhibitor complex, serine kinase, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: O15530
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 34085.36

構造登録者

Whitlow, M.,Adler, M. (登録日: 2005-03-18, 公開日: 2005-04-19, 最終更新日: 2024-10-30)

主引用文献

Feldman, R.I.,Wu, J.M.,Polokoff, M.A.,Kochanny, M.J.,Dinter, H.,Zhu, D.,Biroc, S.L.,Alicke, B.,Bryant, J.,Yuan, S.,Buckman, B.O.,Lentz, D.,Ferrer, M.,Whitlow, M.,Adler, M.,Finster, S.,Chang, Z.,Arnaiz, D.O.
Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1.
J.Biol.Chem., 280:19867-19874, 2005

PubMed Abstract: The phosphoinositide 3-kinase/3-phosphoinositide-dependent kinase 1 (PDK1)/Akt signaling pathway plays a key role in cancer cell growth, survival, and tumor angiogenesis and represents a promising target for anticancer drugs. Here, we describe three potent PDK1 inhibitors, BX-795, BX-912, and BX-320 (IC(50) = 11-30 nm) and their initial biological characterization. The inhibitors blocked PDK1/Akt signaling in tumor cells and inhibited the anchorage-dependent growth of a variety of tumor cell lines in culture or induced apoptosis. A number of cancer cell lines with elevated Akt activity were >30-fold more sensitive to growth inhibition by PDK1 inhibitors in soft agar than on tissue culture plastic, consistent with the cell survival function of the PDK1/Akt signaling pathway, which is particularly important for unattached cells. BX-320 inhibited the growth of LOX melanoma tumors in the lungs of nude mice after injection of tumor cells into the tail vein. The effect of BX-320 on cancer cell growth in vitro and in vivo indicates that PDK1 inhibitors may have clinical utility as anticancer agents.

PubMed: 15772071
DOI: 10.1074/jbc.M501367200

実験手法

X-RAY DIFFRACTION (2.17 Å)