The Pleckstrin homology (PH) domain is a modular structurally conserved protein superfold that binds to plasma membrane phosphoinositide (PtdIns)-3 phosphates causing the host proteins to move to the plasma membrane where they initiate signal transduction cascades critical to cell growth and survival. Ptdlns binding PH domains provide a rich and, as yet, unmined family of unique target sites for anticancer drug discovery. Akt (protein kinase B) is a PH domain containing serine/threonine kinase that is a key component of the PtdIns-3-kinase cell survival signaling pathway. Downstream protein targets phosphorylated by Akt act to inhibit apoptosis and are a major reason cancer cells are resistant to apoptosis. The hypothesis upon which our work is based is that the Ptdlns binding PH domain of Akt provides a novel signaling pathway important for cancer cell survival, and these agents will have antitumor and chemosensitizing activity. This is a novel approach to cancer drug discovery that seeks to block a specific protein/lipid interaction, and thus, prevent the subcellular translocation of the target signaling protein. Using the crystal structure of the PH domain of human Akt and Ins(l,3,4,5)P4, we have conducted in silico screening to identify four novel classes of small molecules that bind selectively to the PH domain of Akt compared to PH domains of other proteins. The lead compounds have been shown to inhibit Akt activation in cancer cells. The objectives of the proposed studies are to obtain molecular validation for Akt relative to other PH domain proteins as a cancer drug target, to use molecular docking and rational drug design to identify specific Akt PH domain inhibitors, to use an iterative process to improve the selectivity of the compounds for the PH domain of Akt, and to identify lead compounds with in vivo antitumor activity for preclinical development. We will focus our studies on pancreatic cancer, a devastating disease for which new treatments are urgently needed. The PtdIns-3-kinase/Akt signaling pathway is upregulated in many pancreatic cancers making it an ideal target for drugs to treat the disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA061015-11
Application #
7458072
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Forry, Suzanne L
Project Start
1994-09-10
Project End
2010-06-30
Budget Start
2008-07-03
Budget End
2009-06-30
Support Year
11
Fiscal Year
2008
Total Cost
$418,157
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Miscellaneous
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Morrow, John K; Du-Cuny, Lei; Chen, Lu et al. (2011) Recent development of anticancer therapeutics targeting Akt. Recent Pat Anticancer Drug Discov 6:146-59
Ahad, Ali Md; Zuohe, Song; Du-Cuny, Lei et al. (2011) Development of sulfonamide AKT PH domain inhibitors. Bioorg Med Chem 19:2046-54
Meuillet, Emmanuelle J; Zuohe, Song; Lemos, Robert et al. (2010) Molecular pharmacology and antitumor activity of PHT-427, a novel Akt/phosphatidylinositide-dependent protein kinase 1 pleckstrin homology domain inhibitor. Mol Cancer Ther 9:706-17
Morrow, John Kenneth; Tian, Longzhang; Zhang, Shuxing (2010) Molecular networks in drug discovery. Crit Rev Biomed Eng 38:143-56
Ihle, Nathan T; Powis, Garth (2010) The biological effects of isoform-specific PI3-kinase inhibition. Curr Opin Drug Discov Devel 13:41-9
Koul, Dimpy; Shen, Ruijun; Kim, Yong-Wan et al. (2010) Cellular and in vivo activity of a novel PI3K inhibitor, PX-866, against human glioblastoma. Neuro Oncol 12:559-69
Ihle, Nathan T; Powis, Garth (2010) Inhibitors of phosphatidylinositol-3-kinase in cancer therapy. Mol Aspects Med 31:135-44
Du-Cuny, Lei; Song, Zuohe; Moses, Sylvestor et al. (2009) Computational modeling of novel inhibitors targeting the Akt pleckstrin homology domain. Bioorg Med Chem 17:6983-92
Ihle, Nathan T; Lemos, Robert; Schwartz, David et al. (2009) Peroxisome proliferator-activated receptor gamma agonist pioglitazone prevents the hyperglycemia caused by phosphatidylinositol 3-kinase pathway inhibition by PX-866 without affecting antitumor activity. Mol Cancer Ther 8:94-100
Moses, Sylvestor A; Ali, M Ahad; Zuohe, Song et al. (2009) In vitro and in vivo activity of novel small-molecule inhibitors targeting the pleckstrin homology domain of protein kinase B/AKT. Cancer Res 69:5073-81

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