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 19 条
[1]   The Akt/PKB family of protein kinases: A review of small molecule inhibitors and progress towards target validation [J].
Barnett, SF ;
Bilodeau, MT ;
Lindsley, CW .
CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2005, 5 (02) :109-125
[2]   Identification and characterization of pleckstrin-homology-domain-dependent and isoenzyme-specific Akt inhibitors [J].
Barnett, SF ;
Defeo-Jones, D ;
Fu, S ;
Hancock, PJ ;
Haskell, KM ;
Jones, RE ;
Kahana, JA ;
Kral, AM ;
Leander, K ;
Lee, LL ;
Malinowski, J ;
McAvoy, EM ;
Nahas, DD ;
Robinson, RG ;
Huber, HE .
BIOCHEMICAL JOURNAL, 2005, 385 :399-408
[3]  
Carson J., 1965, US Pat., Patent No. 3177221
[4]   The development of phosphatidylinositol ether lipid analogues as inhibitors of the serine/threonine kinase, Akt [J].
Gills, JJ ;
Dennis, PA .
EXPERT OPINION ON INVESTIGATIONAL DRUGS, 2004, 13 (07) :787-797
[5]   Synthesis and structure-activity relationship of 3,4′-bispyridinylethylenes:: Discovery of a potent 3-isoquinolinylpyridine inhibitor of protein kinase B (PKB/Akt) for the treatment of cancer [J].
Li, Q ;
Woods, KW ;
Thomas, S ;
Zhu, GD ;
Packard, G ;
Fisher, J ;
Li, TM ;
Gong, JC ;
Dinges, J ;
Song, XH ;
Abrams, J ;
Luo, Y ;
Johnson, EF ;
Shi, Y ;
Liu, XS ;
Klinghofer, V ;
Jong, RD ;
Oltersdorf, T ;
Stoll, VS ;
Jakob, CG ;
Rosenberg, SH ;
Giranda, VL .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (07) :2000-2007
[6]  
Li Qun, 2002, Current Topics in Medicinal Chemistry, V2, P939, DOI 10.2174/1568026023393318
[7]   Allosteric Akt (PKB) inhibitors: discovery and SAR of isozyme selective inhibitors [J].
Lindsley, CW ;
Zhao, ZJ ;
Leister, WH ;
Robinson, RG ;
Barnett, SF ;
Defeo-Jones, D ;
Jones, RE ;
Hartman, GD ;
Huff, JR ;
Huber, HE ;
Duggan, ME .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2005, 15 (03) :761-764
[8]   Potent and selective inhibitors of Akt kinases slow the progress of tumors in vivo [J].
Luo, Y ;
Shoemaker, AR ;
Liu, XS ;
Woods, KW ;
Thomas, SA ;
de Jong, R ;
Han, EK ;
Li, TM ;
Stoll, VS ;
Powlas, JA ;
Oleksijew, A ;
Mitten, MJ ;
Shi, Y ;
Guan, R ;
McGonigal, TP ;
Klinghofer, V ;
Johnson, EF ;
Leverson, JD ;
Bouska, JJ ;
Mamo, M ;
Smith, RA ;
Gramling-Evans, EE ;
Zinker, BA ;
Mika, AK ;
Nguyen, PT ;
Oltersdorf, T ;
Rosenberg, SH ;
Li, Q ;
Giranda, VL .
MOLECULAR CANCER THERAPEUTICS, 2005, 4 (06) :977-986
[9]   Hydroxylation of nitroarenes with alkyl hydroperoxide anions via Vicarious Nucleophilic Substitution of hydrogen [J].
Makosza, M ;
Sienkiewicz, K .
JOURNAL OF ORGANIC CHEMISTRY, 1998, 63 (13) :4199-4208
[10]  
Mazéas D, 1999, HETEROCYCLES, V50, P1065
12