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(3-Chloroacetyl)-indole, a Novel Allosteric AKT Inhibitor, Suppresses Colon Cancer Growth in Vitro and in Vivo

(3-Chloroacetyl)-indole, a Novel Allosteric AKT Inhibitor, Suppresses Colon Cancer Growth in Vitro and in Vivo

Dong Joon Kim, Kanamata Reddy, Myoung Ok Kim, Yan Li, Janos Nadas, Yong-Yeon Cho, Jong-Eun Kim, Jung-Hyun Shim, Nu Ry Song, Andria Carper, Ronald A Lubet, Ann M Bode, Zigang Dong

Cancer Prev Res (Phila). 2011 Nov;4(11):1842-51.

PMID: 21885813

Abstract:

Indole-3-carbinol (I3C) is produced in Brassica vegetables such as broccoli and cabbage and has been shown to inhibit proliferation and induce apoptosis in various cancer cells, including breast, prostate, colon, and leukemia. However, only high doses of I3C were shown to inhibit cell proliferation (IC(50) = 200-300 μmol/L). Our goal here was to develop a more potent antitumor agent by modifying the structure of I3C. We created I3C derivatives and found that (3-chloroacetyl)-indole (3CAI) more strongly inhibited colon cancer cell growth than I3C. In addition, by screening 85 kinases in a competitive kinase assay, we found that 3CAI was a specific AKT inhibitor. AKT is a serine/threonine kinase that plays a pivotal role in promoting transformation and chemoresistance by inducing proliferation and inhibiting apoptosis. Therefore, AKT is regarded as a critical target for cancer therapy. 3ICA, a derivative of I3C, is a potent and specific AKT inhibitor. This compound showed significant inhibition of AKT in an in vitro kinase assay and suppressed expression of AKT direct downstream targets such as mTOR and GSK3β as well as induced growth inhibition and apoptosis in colon cancer cells. In addition, oral administration of this potent AKT inhibitor suppressed cancer cell growth in an in vivo xenograft mouse model.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP28755035-A	3CAI		28755-03-5	Price

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