TY - JOUR
T1 - Akt/protein kinase B signaling inhibitor-2, a selective small molecule inhibitor of Akt signaling with antitumor activity in cancer cells overexpressing Akt
AU - Yang, Lin
AU - Dan, Han C.
AU - Sun, Mei
AU - Liu, Qiyuan
AU - Sun, Xia Meng
AU - Feldman, Richard I.
AU - Hamilton, Andrew D.
AU - Polokoff, Mark
AU - Nicosia, Santo V.
AU - Herlyn, Meenhard
AU - Sebti, Said M.
AU - Cheng, Jin Q.
PY - 2004/7/1
Y1 - 2004/7/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-04-0343
DO - 10.1158/0008-5472.CAN-04-0343
M3 - Article
C2 - 15231645
AN - SCOPUS:3042743988
VL - 64
SP - 4394
EP - 4399
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 13
ER -