Discovery and SAR of oxindole-pyridine-based protein kinase B/Akt inhibitors for treating cancers

被引：51
|
作者：
Zhu, GD [1 ]
Gandhi, VB
Gong, JC
Luo, Y
Liu, XS
Shi, Y
Guan, R
Magnone, SR
Klinghofer, V
Johnson, EF
Bouska, J
Shoemaker, A
Oleksijew, A
Jarvis, K
Park, C
De Jong, R
Oltersdorf, T
Li, Q
Rosenberg, SH
Giranda, VL
机构：
[1] Abbott Labs, GPRD, Canc Res, Abbott Pk, IL 60064 USA
[2] Abbott Labs, GPRD, Struct Biol, Abbott Pk, IL 60064 USA
[3] IDUN Pharmaceut Inc, San Diego, CA 92121 USA
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2006年 / 16卷 / 13期
关键词：
Akt inhibitor; protein kinase B; PKB; GSK3; FL5.12-Akt; anticancer;
D O I：
10.1016/j.bmcl.2006.04.005
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
We describe a series of potent and selective oxindole-pyridine-based protein kinase B/Akt inhibitors. The most potent compound 11n in this series demonstrated an IC50 of 0.17 nM against Akt1 and more than 100-fold selectivity over other Akt isozymes. The selectivity against other protein kinases was highly dependent on the C-3 substitutions at the oxindole scaffold, with unsubstituted 9e or 3-furan-2-ylmethylene (11n) more selective and 3-(1H-pyrrol-2-yl)methylene (11f) or 3-(1H-imidazol-2-yl)methylene (Ilk) less selective. In a mouse xenograft model, 9d, 11f, and 11n inhibited tumor growth but with accompanying toxicity. (c) 2006 Elsevier Ltd. All rights reserved.
引用
收藏
页码：3424 / 3429
页数：6
相关论文
共 50 条
  • [31] Discovery of pyridine amide based inhibitors of interleukin receptor-associated kinase 4 (IRAK4) for the treatment of lupus
    Hynes, John
    Nair, Satheesh
    Pitts, William
    Bhide, Rajeev
    Schmidt, Robert
    Spergel, Steven
    Paidi, Venkat Ram Reddy
    Kumar, Sreekantha Ratna
    Sistla, Ramesh
    Santella, Joseph
    Gardner, Daniel
    Wu, Hong
    Duncia, John
    Murugesan, Natesan
    Tino, Joseph
    Carter, Percy
    Carman, Julie
    Dudhgaonkar, Shailesh
    Srivastava, Ratika
    Deborah, Furst
    Goldstine, Christine
    Skala, Stacy
    Li, Xin
    Maddi, Srinivas
    Saxena, Ajay
    Palanisamy, Kamalavenkatesh
    Chimalakonda, Anjaneya
    Ruepp, Stefan
    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2016, 252
  • [32] Structure-based discovery of novel flavonol inhibitors of human protein kinase CK2
    Golub, Andriy G.
    Bdzhola, Volodymyr G.
    Kyshenia, Yaroslav V.
    Sapelkin, Vladislav M.
    Prykhod'ko, Andriy O.
    Kukharenko, Olexander P.
    Ostrynska, Olga V.
    Yarmoluk, Sergiy M.
    MOLECULAR AND CELLULAR BIOCHEMISTRY, 2011, 356 (1-2) : 107 - 115
  • [33] Identification of small-molecule inhibitors of protein kinase B (PKB/AKT) in an AlphaScreen™ high-throughput screen
    Burns, Samantha
    Travers, Jonathan
    Collins, Ian
    Rowlands, Martin G.
    Newbatt, Yvette
    Thompson, Neil
    Garrett, Michelle D.
    Workman, Paul
    Aherne, Wynne
    JOURNAL OF BIOMOLECULAR SCREENING, 2006, 11 (07) : 822 - 827
  • [34] Structure-based discovery of novel flavonol inhibitors of human protein kinase CK2
    Andriy G. Golub
    Volodymyr G. Bdzhola
    Yaroslav V. Kyshenia
    Vladislav M. Sapelkin
    Andriy O. Prykhod’ko
    Olexander P. Kukharenko
    Olga V. Ostrynska
    Sergiy M. Yarmoluk
    Molecular and Cellular Biochemistry, 2011, 356 : 107 - 115
  • [35] 3D QSAR and HQSAR analysis of protein kinase B (PKB/Akt) inhibitors using various alignment methods
    Vyas, Vivek K.
    Ghate, Manjunath
    Gupta, Nirzari
    ARABIAN JOURNAL OF CHEMISTRY, 2017, 10 : S2182 - S2195
  • [36] In vitro and In vivo Activity of Novel Small-Molecule Inhibitors Targeting the Pleckstrin Homology Domain of Protein Kinase B/AKT
    Moses, Sylvestor A.
    Ali, M. Ahad
    Song Zuohe
    Lei Du-Cuny
    Zhou, Li Li
    Lemos, Robert
    Ihle, Nathan
    Skillman, A. Geoffrey
    Zhang, Shuxing
    Mash, Eugene A.
    Powis, Garth
    Meuillet, Emmanuelle J.
    CANCER RESEARCH, 2009, 69 (12) : 5073 - 5081
  • [37] An in silico approach to identify novel and potential Akt1 (protein kinase B-alpha) inhibitors as anticancer drugs
    Etikyala, Umadevi
    Reddyrajula, Rajkumar
    Vani, T.
    Kuchana, Vinutha
    Dalimba, Udayakumar
    Manga, Vijjulatha
    MOLECULAR DIVERSITY, 2025, 29 (02) : 1009 - 1032
  • [38] Protein kinase B/Akt antagonists as antitumor agents part 4: Syntheses of potent, highly selective and orally bioavailable Akt inhibitors with reduced toxicity.
    Gong, J
    Gandhi, VB
    Li, T
    Luo, Y
    Shi, Y
    Liu, X
    Klinghofer, V
    Bouska, J
    Olson, A
    Shoemaker, A
    Stoll, VS
    Lubbers, NL
    Polakowski, J
    Ballaron, S
    Campbell, TJ
    De Jong, R
    Oltersdorf, T
    Li, Q
    Rosenberg, SH
    Giranda, V
    Zhu, GD
    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2005, 229 : U133 - U133
  • [39] Pharmacophore based High Throughput Virtual Screening towards the Discovery of Novel BLK (B-lymphocyte kinase)tyrosine Kinase Inhibitors
    Sumera, Sana
    Srinivasan, Sanjai
    Harshitha, B., V
    Biradar, Sharanagoud
    Patil, Shankarrao
    INDIAN JOURNAL OF PHARMACEUTICAL EDUCATION AND RESEARCH, 2023, 57 (01) : S174 - S182
  • [40] The discovery of imidazo[4,5-c]pyridine-2-ones as selective inhibitors of DNA-dependent protein kinase and effective radiosensitisers
    Hay, M.
    Hong, C.
    Liew, L.
    Dickson, B.
    Wong, W.
    O'Brien-Gortner, S.
    Airey, R.
    Wilson, W.
    Jamieson, S.
    EUROPEAN JOURNAL OF CANCER, 2024, 211 : S62 - S62
12345