TARGET-GUIDED DEVELOPMENT OF SPECIFIC AKT INHIBITORS

Summary

Principal Investigator: Peter Vogt
Abstract: DESCRIPTION (provided by applicant): 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
Funding Period: 2005-09-23 - 2010-06-30
more information: NIH RePORT

Top Publications

  1. pmc Class I PI3K in oncogenic cellular transformation
    L Zhao
    Division of Oncovirology, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
    Oncogene 27:5486-96. 2008
  2. pmc PI3K: from the bench to the clinic and back
    Bart Vanhaesebroeck
    University of London, London, EC1M 6BQ, UK
    Curr Top Microbiol Immunol 347:1-19. 2010
  3. pmc Phosphatidylinositol 3-kinase: the oncoprotein
    Peter K Vogt
    Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
    Curr Top Microbiol Immunol 347:79-104. 2010
  4. pmc Hot-spot mutations in p110alpha of phosphatidylinositol 3-kinase (pI3K): differential interactions with the regulatory subunit p85 and with RAS
    Li Zhao
    Department of Molecular and Experimental Medicine, The Scripps Research Institute La Jolla, CA USA
    Cell Cycle 9:596-600. 2010
  5. pmc Phosphatidylinositol 4,5-bisphosphate-specific AKT1 is oncogenic
    Nadine Dannemann
    The Scripps Research Institute, Molecular and Experimental Medicine, La Jolla, California 92037, USA
    Int J Cancer 127:239-44. 2010

Detail Information

Publications5

  1. pmc Class I PI3K in oncogenic cellular transformation
    L Zhao
    Division of Oncovirology, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
    Oncogene 27:5486-96. 2008
    ..Isoform-selective inhibitors have been identified. Inhibitors that target exclusively the cancer-specific mutants of p110 alpha constitute an important goal and challenge for current drug development...
  2. pmc PI3K: from the bench to the clinic and back
    Bart Vanhaesebroeck
    University of London, London, EC1M 6BQ, UK
    Curr Top Microbiol Immunol 347:1-19. 2010
    ..PI3K will most likely be no exception. Below, we describe some of these early "surprises" and how these inform and shape basic science investigations...
  3. pmc Phosphatidylinositol 3-kinase: the oncoprotein
    Peter K Vogt
    Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
    Curr Top Microbiol Immunol 347:79-104. 2010
    ..TOR is an integrator of growth and of metabolic inputs. In complex with the raptor protein (TORC1), it controls cap-dependent translation, and this function is essential for PI3K-initiated oncogenesis...
  4. pmc Hot-spot mutations in p110alpha of phosphatidylinositol 3-kinase (pI3K): differential interactions with the regulatory subunit p85 and with RAS
    Li Zhao
    Department of Molecular and Experimental Medicine, The Scripps Research Institute La Jolla, CA USA
    Cell Cycle 9:596-600. 2010
    ..The gain of function induced by helical domain mutations requires interaction with RAS-Gtp. In contrast, the kinase domain mutation is active in the absence of RAS-Gtp binding, but depends on the interaction with p85...
  5. pmc Phosphatidylinositol 4,5-bisphosphate-specific AKT1 is oncogenic
    Nadine Dannemann
    The Scripps Research Institute, Molecular and Experimental Medicine, La Jolla, California 92037, USA
    Int J Cancer 127:239-44. 2010
    ..Gain-of-function mutants of AKT1 may not be affected by PI3K inhibitors that are currently in development. Therefore, AKT1 remains a distinct and important cancer target...