Akt/protein kinase B signaling inhibitor-2, a selective small molecule inhibitor of Akt signaling with antitumor activity in cancer cells overexpressing Akt

Lin Yang, Han C. Dan, Mei Sun, Qiyuan Liu, Xia Meng Sun, Richard I. Feldman, Andrew Hamilton, Mark Polokoff, Santo V. Nicosia, Meenhard Herlyn, Said M. Sebti, Jin Q. Cheng

Research output: Contribution to journalArticle

Abstract

Accumulated studies have shown that activation of the Akt pathway plays a pivotal role in malignant transformation and chemoresistance by inducing cell survival, growth, migration, and angiogenesis. Therefore, Akt is believed to be a critical target for cancer intervention. Here, we report the discovery of a small molecule Akt pathway inhibitor, Akt/ protein kinase B signaling inhibitor-2 (API-2), by screening the National Cancer Institute Diversity Set. API-2 suppressed the kinase activity and phosphorylation level of Akt. The inhibition of Akt kinase resulted in suppression of cell growth and induction of apoptosis in human cancer cells that harbor constitutively activated Akt due to overexpression of Akt or other genetic alterations such as PTEN mutation. API-2 is highly selective for Akt and does not inhibit the activation of phosphatidylinositol 3′-kinase, phosphoinositide-dependent kinase-1, protein kinase C, serum-and glucocorticold-inducible kinase, protein kinase A, signal transducer and activators of transcription 3, extracellular signal-regulated kinase-1/2, or c-Jun NH2-terminal kinase. Furthermore, API-2 potently inhibited tumor growth in nude mice of human cancer cells in which Akt is aberrantly expressed/activated but not of those cancer cells in which it is not. These findings provide strong evidence for pharmacologically targeting Akt for anticancer drug discovery.

Original languageEnglish (US)
Pages (from-to)4394-4399
Number of pages6
JournalCancer Research
Volume64
Issue number13
DOIs
StatePublished - Jul 1 2004

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Neoplasms
Phosphotransferases
Growth
Phosphatidylinositol 3-Kinase
STAT3 Transcription Factor
1-Phosphatidylinositol 4-Kinase
Mitogen-Activated Protein Kinase 3
National Cancer Institute (U.S.)
JNK Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinase 1
Drug Discovery
Cyclic AMP-Dependent Protein Kinases
Nude Mice
Protein Kinase C
Cell Survival
Phosphorylation
API-2 nucleoside
Apoptosis
Mutation
API 2

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Akt/protein kinase B signaling inhibitor-2, a selective small molecule inhibitor of Akt signaling with antitumor activity in cancer cells overexpressing Akt. / Yang, Lin; Dan, Han C.; Sun, Mei; Liu, Qiyuan; Sun, Xia Meng; Feldman, Richard I.; Hamilton, Andrew; Polokoff, Mark; Nicosia, Santo V.; Herlyn, Meenhard; Sebti, Said M.; Cheng, Jin Q.

In: Cancer Research, Vol. 64, No. 13, 01.07.2004, p. 4394-4399.

Research output: Contribution to journalArticle

Yang, L, Dan, HC, Sun, M, Liu, Q, Sun, XM, Feldman, RI, Hamilton, A, Polokoff, M, Nicosia, SV, Herlyn, M, Sebti, SM & Cheng, JQ 2004, 'Akt/protein kinase B signaling inhibitor-2, a selective small molecule inhibitor of Akt signaling with antitumor activity in cancer cells overexpressing Akt', Cancer Research, vol. 64, no. 13, pp. 4394-4399. https://doi.org/10.1158/0008-5472.CAN-04-0343
Yang, Lin ; Dan, Han C. ; Sun, Mei ; Liu, Qiyuan ; Sun, Xia Meng ; Feldman, Richard I. ; Hamilton, Andrew ; Polokoff, Mark ; Nicosia, Santo V. ; Herlyn, Meenhard ; Sebti, Said M. ; Cheng, Jin Q. / Akt/protein kinase B signaling inhibitor-2, a selective small molecule inhibitor of Akt signaling with antitumor activity in cancer cells overexpressing Akt. In: Cancer Research. 2004 ; Vol. 64, No. 13. pp. 4394-4399.
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