DC120, a novel and potent inhibitor of AKT kinase, induces tumor cell apoptosis and suppresses tumor growth

Molecular Pharmacology
Rong DengXiao-Feng Zhu

Abstract

Protein kinase B/AKT kinase is the core component of the phosphatidylinositol 3-kinase/AKT signaling pathway, which is frequently hyperactivated in human cancers. We designed and synthesized a series of 2-pyrimidyl-5-amidothiazole compounds based on the ATP binding site of AKT, and the most potent compound, (S)-N-(1-amino-3-(2,4-dichlorophenyl)propan-2-yl)-2-(2-(methylamino)pyrimidin-4-yl)thiazole-5-carboxamide (DC120), was identified to inhibit AKT activity in vitro with an EC(50) of 153 nM by a fluorescence resonance energy transfer-based Z'-LYTE assay. The antitumor effect of DC120 was tested on human CNE2 and MDA-MB-453 cell lines and the CNE2 xenograft model. The results showed that DC120 could obviously inhibit the proliferation of CNE2 and MDA-MB-453 cells via induction of apoptosis, with the evidence of increases in sub-G(1) and annexin V-positive cells, characteristic morphologic changes of apoptosis in the nucleus, and cleaved caspase-3. Further study showed that MDA-MB-453 cells transfected with constitutively activated AKT1 were more sensitive to DC120,whereas CNE2 cells with knockdown of AKT1 expression by short hairpin RNA were more resistant to DC120. Of more importance, DC120 partially attenuated the phosphoryla...Continue Reading

References

Jun 16, 2005·Molecular Cancer Therapeutics·Yan LuoVincent L Giranda
Aug 13, 2005·Advances in Cancer Research·Alfonso BellacosaJoseph Robert Testa
Dec 21, 2005·The Journal of Cell Biology·Hanna Y IrieJoan S Brugge
Jun 13, 2006·Bioorganic & Medicinal Chemistry Letters·Xiaodong LinA B Jefferson
Jun 9, 2007·Expert Review of Anticancer Therapy·Jin-Young ParkRobert H Weiss
Jul 3, 2007·Cell·Brendan D Manning, Lewis C Cantley
Aug 19, 2007·Molecular Cancer Therapeutics·James A CrowellJudith R Fay
Feb 22, 2008·Current Cancer Drug Targets·Eriko TokunagaYoshihiko Maehara
Mar 17, 2009·Bioorganic & Medicinal Chemistry Letters·Mark A SeefeldDirk A Heerding
May 26, 2009·Nature Chemical Biology·Tatsuya OkuzumiKevan M Shokat
Jul 25, 2009·Nature Reviews. Cancer·Jeffrey A Engelman
Dec 10, 2009·Molecular Cancer Therapeutics·Wen-Jun ZhouXiao-Feng Zhu
Sep 15, 2010·International Journal of Cancer. Journal International Du Cancer·Lingyun Wei, Zhifei Xu
Mar 4, 2011·Proceedings of the National Academy of Sciences of the United States of America·Anindita ChakrabartyCarlos L Arteaga
May 19, 2011·Nature Reviews. Clinical Oncology·Filip JankuRazelle Kurzrock
May 28, 2011·Breast Cancer Research and Treatment·Kevin KalinskyMary Ellen Moynahan
May 31, 2011·Cellular Signalling·Ingeborg HersJeremy M Tavaré
Jul 22, 2011·Molecular Pharmacology·Jason Boyang Wu, Jean C Shih
Sep 21, 2011·International Journal of Cancer. Journal International Du Cancer·Vicki L J WhitehallBarbara A Leggett
Oct 13, 2011·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Paul G RichardsonKenneth C Anderson
Dec 17, 2011·Bioorganic & Medicinal Chemistry Letters·Shaohua ChangKe Ding

❮ Previous
Next ❯

Citations

Dec 25, 2015·International Journal of Oncology·George Mihai NitulescuAristidis M Tsatsakis
Jun 3, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Mehlika Dilek AltıntopAhmet Özdemir

❮ Previous
Next ❯

Related Concepts

Related Feeds

Apoptosis in Cancer

Apoptosis is an important mechanism in cancer. By evading apoptosis, tumors can continue to grow without regulation and metastasize systemically. Many therapies are evaluating the use of pro-apoptotic activation to eliminate cancer growth. Here is the latest research on apoptosis in cancer.

AKT Pathway

This feed focuses on the AKT serine/threonine kinase, which is an important signaling pathway involved in processes such as glucose metabolism and cell survival.

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis