We plan to produce highly specific and potent inhibitors of the Akt kinase using in situ click chemistry, a new technique that employs the target protein for assembling inhibitors from simple precursors. Akt is a serinethreonine protein kinase that plays a central role in the control of cell growth and replication. It shows a gain of function in about 50 percent of the non-small cell lung cancers. Cancer of the breast, prostate and pancreas also show involvement of Akt. The potential clinical indications for Akt inhibitors are, therefore, wide and numerous. In situ click chemistry allows the generation of biligand inhibitors of unsurpassed specificity and potency for Akt. The principle of this method is to design two ligands targeted to two neighboring sites on the enzyme. The ligands are equipped with complementary reactive groups, and upon simultaneous binding of the two ligands to their targets, these reactive groups form a covalent connection, causing the formation of a biligand, which engages in multiple interactions with the protein's binding pockets.
The specific aims are: (1) Design and produce libraries of compounds that are targeted at the ATP-binding site and that carry additional functional groups for in situ click chemistry; screen these libraries in vitro for ATP-competitive Akt inhibitors that will be used as anchor molecules. (2) Perform in situ click chemistry with anchor molecules bound to Akt and generate bivalent Akt ligands. (3) Determine potency and specificity of bivalent Akt inhibitors, perform cell-based assays for interference with Akt-induced oncogenic transformation. (4) Investigate the structure-activity relationship through in situ click chemistry and optimize inhibitors for potency, selectivity and cell-based activity

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA115521-01
Application #
6955179
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Knowlton, John R
Project Start
2005-09-23
Project End
2009-06-30
Budget Start
2005-09-23
Budget End
2006-06-30
Support Year
1
Fiscal Year
2005
Total Cost
$290,982
Indirect Cost
Name
University of California Los Angeles
Department
Pharmacology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Vanhaesebroeck, Bart; Vogt, Peter K; Rommel, Christian (2010) PI3K: from the bench to the clinic and back. Curr Top Microbiol Immunol 347:1-19
Zhao, Li; Vogt, Peter K (2010) Hot-spot mutations in p110alpha of phosphatidylinositol 3-kinase (pI3K): differential interactions with the regulatory subunit p85 and with RAS. Cell Cycle 9:596-600
Vogt, Peter K; Hart, Jonathan R; Gymnopoulos, Marco et al. (2010) Phosphatidylinositol 3-kinase: the oncoprotein. Curr Top Microbiol Immunol 347:79-104
Dannemann, Nadine; Hart, Jonathan Ross; Ueno, Lynn et al. (2010) Phosphatidylinositol 4,5-bisphosphate-specific AKT1 is oncogenic. Int J Cancer 127:239-44
Zhao, L; Vogt, P K (2008) Class I PI3K in oncogenic cellular transformation. Oncogene 27:5486-96