3RWQ

Discovery of a Novel, Potent and Selective Inhibitor of 3-Phosphoinositide Dependent Kinase (PDK1)

3RWQ の概要

• エントリーDOI: 10.2210/pdb3rwq/pdb
• 関連するPDBエントリー: 3RWP 3SC1
• 分子名称: 3-phosphoinositide-dependent protein kinase 1, [4-amino-7-(propan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl](6-{[2-(pyridin-3-yl)ethyl]amino}pyrazin-2-yl)methanone, GLYCEROL, ... (5 entities in total)
• 機能のキーワード: kinase domain, transferase, phosphoserine: sep, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 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: 36906.91

構造登録者

Kazmirski, S.,Kohls, D. (登録日: 2011-05-09, 公開日: 2011-11-16, 最終更新日: 2024-10-09)

主引用文献

Murphy, S.T.,Alton, G.,Bailey, S.,Baxi, S.M.,Burke, B.J.,Chappie, T.A.,Ermolieff, J.,Ferre, R.,Greasley, S.,Hickey, M.,Humphrey, J.,Kablaoui, N.,Kath, J.,Kazmirski, S.,Kraus, M.,Kupchinsky, S.,Li, J.,Lingardo, L.,Marx, M.A.,Richter, D.,Tanis, S.P.,Tran, K.,Vernier, W.,Xie, Z.,Yin, M.J.,Yu, X.H.
Discovery of Novel, Potent, and Selective Inhibitors of 3-Phosphoinositide-Dependent Kinase (PDK1).
J.Med.Chem., 54:8490-8500, 2011

PubMed Abstract: Analogues substituted with various amines at the 6-position of the pyrazine ring on (4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrazin-2-ylmethanone were discovered as potent and selective inhibitors of PDK1 with potential as anticancer agents. An early lead with 2-pyridine-3-ylethylamine as the pyrazine substituent showed moderate potency and selectivity. Structure-based drug design led to improved potency and selectivity against PI3Kα through a combination of cyclizing the ethylene spacer into a saturated, five-membered ring and substituting on the 4-position of the aryl ring with a fluorine. ADME properties were improved by lowering the lipophilicity with heteroatom replacements in the saturated, five-membered ring. The optimized analogues have a PDK1 Ki of 1 nM and >100-fold selectivity against PI3K/AKT-pathway kinases. The cellular potency of these analogues was assessed by the inhibition of AKT phosphorylation (T308) and by their antiproliferation activity against a number of tumor cell lines.

PubMed: 22040023
DOI: 10.1021/jm201019k

実験手法

X-RAY DIFFRACTION (2.55 Å)