Prev. Article Next Article Table of Contents

Article

A Novel Substrate Mimetic Inhibitor of PKB/Akt Inhibits Prostate Cancer Tumor Growth in Mice by Blocking the PKB Pathway

Pninit Litman,^‡^§ Osnat Ohne,^‡^§ Shirly Ben-Yaakov,^§ Liron Shemesh-Darvish,^§ Tamar Yechezkel,^§ Yosef Salitra,^§ Shai Rubnov,^§ Ilana Cohen,^§ Hanoch Senderowitz,^§ Dvora Kidron, Oded Livnah, Alexander Levitzki, and Nurit Livnah*^§

DeveloGen Israel Ltd., Kiryat Weizmann, Building 16, Rehovot, Israel 76326, Unit of Pathology, Meir Medical Center, Kfar Saba, Israel, and Wolfson Centre of Applied Structural Biology and Unit of Cellular Signaling, Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 91904, Israel

Biochemistry, 2007, 46 (16), pp 4716–4724

DOI: 10.1021/bi061928s

Publication Date (Web): March 31, 2007

‡

These authors contributed equally to this work.

DeveloGen Israel Ltd.

Meir Medical Center.

Hebrew University of Jerusalem.

To whom correspondence should be addressed. Tel: 972-8-9387774. Fax: 972-8-9300083. E-mail: livnah@develogen.com.

Abstract

We describe a novel, potent peptide substrate mimetic inhibitor of protein kinase B (PKB/Akt). The compound selectively kills prostate cancer cells, in which PKB is highly activated, but not normal cells, or cancer cells in which PKB is not activated. The inhibitor induces apoptosis and inhibits the phosphorylation of PKB substrates in prostate cancer cell lines and significantly increases the efficacy of chemotherapy agents to induce prostate cancer cell death, when given in combination. In vivo, the inhibitor exhibits a strong antitumor effect in two prostate cancer mouse models. Moreover, treated animals develop significantly less lung metastases compared to untreated ones, and the effect is accompanied by a significant decrease in blood PSA [prostate-specific antigen] levels in treated animals. This compound and its potential analogues may be developed into novel, potent, and safe anticancer agents, both as stand-alone treatment and in combination with other chemotherapy agents.

View: Full Text HTML | Hi-Res PDF

Tools

SciFinder Links

History

Published In Issue April 24, 2007
Received September 17, 2006
Revised Manuscript Received February 14, 2007

Recommend & Share

Related Content

Molecular Recognition of Protein Kinase Binding Pockets for Design of Potent and Selective Kinase InhibitorsJournal of Medicinal Chemistry
- Molecular Recognition of Protein Kinase Binding Pockets for Design of Potent and Selective Kinase Inhibitors
  Jeffrey Jie-Lou Liao
  Journal of Medicinal Chemistry 2007 50 (3), pp 409–424
  Abstract | Full Text HTML | Hi-Res PDF
Tuning a Three-Component Reaction For Trapping Kinase Substrate ComplexesJournal of the American Chemical Society
- Tuning a Three-Component Reaction For Trapping Kinase Substrate Complexes
  Alexander V. Statsuk, Dustin J. Maly, Markus A. Seeliger, Miles A. Fabian, William H. Biggs, III., David J. Lockhart, Patrick P. Zarrinkar, John Kuriyan and Kevan M. Shokat
  Journal of the American Chemical Society 2008 130 (51), pp 17568–17574
  Abstract: The upstream protein kinases responsible for thousands of phosphorylation events in the phosphoproteome remain to be discovered. We developed a three-component chemical reaction which converts the transient noncovalent substrate−kinase complex into a ...
  Abstract | Full Text HTML | PDF w/ Links | Hi-Res PDF
Identification of 4-(2-(4-Amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a Novel Inhibitor of AKT KinaseJournal of Medicinal Chemistry
- Identification of 4-(2-(4-Amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a Novel Inhibitor of AKT Kinase
  Dirk A. Heerding, Nelson Rhodes, Jack D. Leber, Tammy J. Clark, Richard M. Keenan, Louis V. Lafrance, Mei Li, Igor G. Safonov, Dennis T. Takata, Joseph W. Venslavsky, Dennis S. Yamashita, Anthony E. Choudhry, Robert A. Copeland, Zhihong Lai, Michael D. Schaber, Peter J. Tummino, Susan L. Strum, Edgar R. Wood, Derek R. Duckett, Derek Eberwein, Victoria B. Knick, Timothy J. Lansing, Randy T. McConnell, ShuYun Zhang, Elisabeth A. Minthorn, Nestor O. Concha, Gregory L. Warren and Rakesh Kumar
  Journal of Medicinal Chemistry 2008 51 (18), pp 5663–5679
  Abstract: Overexpression of AKT has an antiapoptotic effect in many cell types, and expression of dominant negative AKT blocks the ability of a variety of growth factors to promote survival. Therefore, inhibitors of AKT kinase activity might be useful as ...
  Abstract | Full Text HTML | PDF w/ Links | Hi-Res PDF

Article

A Novel Substrate Mimetic Inhibitor of PKB/Akt Inhibits Prostate Cancer Tumor Growth in Mice by Blocking the PKB Pathway

Abstract

Tools

SciFinder Links

History

Recommend & Share

Related Content

Molecular Recognition of Protein Kinase Binding Pockets for Design of Potent and Selective Kinase Inhibitors

Tuning a Three-Component Reaction For Trapping Kinase Substrate Complexes

Identification of 4-(2-(4-Amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a Novel Inhibitor of AKT Kinase

Other ACS content by these authors:

JOURNALS

BOOKS

MAGAZINE

COMMUNITIES

DIRECTORIES & DATABASES