Discovery and biological activity of 6BrCaQ as an inhibitor of the Hsp90 protein folding machinery.

Université Paris-Sud, CNRS, BioCIS-UMR 8076, Laboratoire de Chimie Thérapeutique, Faculté de Pharmacie, Châtenay-Malabry, France.
ChemMedChem (Impact Factor: 2.84). 03/2011; 6(5):804-15. DOI: 10.1002/cmdc.201000489
Source: PubMed

ABSTRACT Heat shock protein 90 (Hsp90) is a significant target in the development of rational cancer therapy, due to its role at the crossroads of multiple signaling pathways associated with cell proliferation and viability. Here, a novel series of Hsp90 inhibitors containing a quinolein-2-one scaffold was synthesized and evaluated in cell proliferation assays. Results from these structure-activity relationships studies enabled identification of the simplified 3-aminoquinolein-2-one analogue 2 b (6BrCaQ), which manifests micromolar activity against a panel of cancer cell lines. The molecular signature of Hsp90 inhibition was assessed by depletion of standard known Hsp90 client proteins. Finally, processing and activation of caspases 7, 8, and 9, and the subsequent cleavage of PARP by 6BrCaQ, suggest stimulation of apoptosis through both extrinsic and intrinsic pathways.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Inhibition of Hsp90 C-terminal function is an advantageous therapeutic paradigm for the treatment of cancer. Currently, the majority of Hsp90 C-terminal inhibitors are derived from novobiocin, a natural product traditionally used as an antibiotic. Assisted by molecular docking studies, a scaffold containing a biphenyl moiety in lieu of the coumarin ring system found in novobiocin was identified for development of new Hsp90 C-terminal inhibitors. Initial structure-activity studies led to derivatives that manifest good antiproliferative activity against two breast cancer cell lines through Hsp90 inhibition. This platform serves as a scaffold upon which new Hsp90 C-terminal inhibitors can be readily assembled for further investigation.
    ACS Medicinal Chemistry Letters 01/2014; · 3.31 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: INTRODUCTION: Heat-shock protein 90 (Hsp90) is a validated novel anticancer target with unique features. As a molecular chaperone, Hsp90 is implicated in maintaining the conformation, stability, activity and cellular localization of several key oncogenic client proteins that are involved in signal transduction pathways leading to proliferation, cell-cycle progression, apoptosis, angiogenesis and metastasis. As a result, inhibitors of Hsp90 achieve their promising anticancer activity through disruption of the Hsp90 protein function, thereby freezing the chaperone cycle; this in turn decreases the affinity of Hsp90 for client proteins, thus leading to proteasome-mediated degradation of oncogenic client proteins within cancer cells. AREAS COVERED: This review provides recent background information on Hsp90 inhibitors. It also highlights a panel of compounds of interest reported in patents and discusses the clinical results of the promising drug candidates. EXPERT OPINION: In the past 5 years, Hsp90 inhibitors have remained the focus of much interest as new potential anticancer agents. A large variety of scaffolds were studied in both academia and industry. Consequently, these significant research efforts have provided several promising drug candidates for further clinical development. Further progress in the development of Hsp90 inhibitors, combined with a deeper understanding of the chaperon characteristics, strengthens their promise in cancer therapy.
    Expert Opinion on Therapeutic Patents 06/2011; 21(10):1501-42. · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Biologically active 3H-pyrrolo[2,3-c]quinolin-4(5H)-ones have been synthesized in an efficient and concise manner utilizing readily available 4-hydroxyquinolin-2(1H)-ones as the starting material. The key strategy relies on the construction of the pyrrole ring through the palladium catalyzed sequential cross-coupling reaction and cyclization process.
    Organic & Biomolecular Chemistry 09/2013; · 3.57 Impact Factor


Available from
May 19, 2014