3OW4

Discovery of dihydrothieno- and dihydrofuropyrimidines as potent pan Akt inhibitors

3OW4 の概要

• エントリーDOI: 10.2210/pdb3ow4/pdb
• 関連するPDBエントリー: 3OW3
• 分子名称: RAC-alpha serine/threonine-protein kinase, GSK 3 beta peptide, (2R)-3-(1H-indol-3-yl)-1-{4-[(5S)-5-methyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]piperazin-1-yl}-1-oxopropan-2-amine, ... (4 entities in total)
• 機能のキーワード: serine-threonine kinase, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P31749
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 82025.47

構造登録者

Dizon, F.,Wu, W.,Vigers, G.P.A.,Brandhuber, B.J. (登録日: 2010-09-17, 公開日: 2010-11-10, 最終更新日: 2024-11-06)

主引用文献

Bencsik, J.R.,Xiao, D.,Blake, J.F.,Kallan, N.C.,Mitchell, I.S.,Spencer, K.L.,Xu, R.,Gloor, S.L.,Martinson, M.,Risom, T.,Woessner, R.D.,Dizon, F.,Wu, W.I.,Vigers, G.P.,Brandhuber, B.J.,Skelton, N.J.,Prior, W.W.,Murray, L.J.
Discovery of dihydrothieno- and dihydrofuropyrimidines as potent pan Akt inhibitors.
Bioorg.Med.Chem.Lett., 20:7037-7041, 2010

PubMed Abstract: Herein we report the discovery and synthesis of a novel series of dihydrothieno- and dihydrofuropyrimidines (2 and 3) as potent pan Akt inhibitors. Utilizing previous SAR and analysis of the amino acid sequences in the binding site we have designed inhibitors displaying increased PKA and general kinase selectivity with improved tolerability compared to the progenitor pyrrolopyrimidine (1). A representative dihydrothieno compound (34) was advanced into a PC3-NCI prostate mouse tumor model in which it demonstrated a dose-dependent reduction in tumor growth and stasis when dosed orally daily at 200 mg/kg.

PubMed: 20971641
DOI: 10.1016/j.bmcl.2010.09.112

実験手法

X-RAY DIFFRACTION (2.6 Å)