Mol Cell：NCI科学家发现分子伴侣Hsp90的分子开关
Mesh-terms: 1-Phosphatidylinositol 3-Kinase, metabolism; Animals; Antineoplastic Agents, pharmacology; Benzoquinones, pharmacology; COS Cells; Cell Line, Tumor; Cercopithecus aethiops; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases, metabolism; Gene Expression Regulation, Enzymologic; HSP90 Heat-Shock Proteins, antagonists & inhibitors; Humans; Lactams, Macrocyclic, pharmacology; Molecular Chaperones, chemistry; Proto-Oncogene Proteins c-akt, metabolism; Signal Transduction; Time Factors; src-Family Kinases, metabolism;
Curr Top Med Chem. 2006 ;6:1163-71 16842153
Using natural product inhibitors to validate hsp90 as a molecular target in cancer.
Len Neckers
Heat shock protein 90 (Hsp90) is a molecular chaperone whose association is required for stability and function of multiple mutated, chimeric, and over-expressed signaling proteins that promote cancer cell growth and/or survival. Hsp90 client proteins include telomerase, mutated p53, Bcr-Abl, Raf-1, Akt, HER2/Neu (ErbB2), mutated B-Raf, mutated EGF receptor, and HIF-1alpha. Hsp90 inhibitors, by interacting specifically with a single molecular target, cause inactivation, destabilization and eventual degradation of Hsp90 client proteins, and they have shown promising anti-tumor activity in various preclinical tumor models. One Hsp90 inhibitor, 17-AAG, is currently in Phase II clinical trial and other inhibitors will shortly be entering the clinic. Hsp90 inhibitors are unique in that, although they are directed towards a specific molecular target, they simultaneously inhibit multiple signaling pathways on which cancer cells depend for growth and survival. Identification of benzoquinone ansamycins as the first Hsp90 inhibitors allowed investigators to determine the biologic effects, at first in vitro and then in vivo, of pharmacologic inhibition of Hsp90. These studies rapidly enhanced our understanding of Hsp90 function and led to the identification of radicicol as a structurally distinct Hsp90 inhibitor. Additional target-based screening uncovered novobiocin as a third structurally distinct small molecule with Hsp90 inhibitory properties. Use of novobiocin, in turn, led to identification of a previously uncharacterized C-terminal ATP binding site in the chaperone. Small molecule inhibitors of Hsp90 have been very useful in understanding Hsp90 biology and in validating this protein as a molecular target for anti-cancer drug development.
Med Chem. 2006 Mar ;2:169-74 16787365
Curcumin is an inhibitor of p300 histone acetylatransferase.
Monica G Marcu , Yun-Jin Jung , Sunmin Lee , Eun-Joo Chung , Min-Jung Lee , Jane Trepel , Len Neckers
Histone acetyltransferases (HATs), and p300/CBP in particular, have been implicated in cancer cell growth and survival, and as such, HATs represent novel, therapeutically relevant molecular targets for drug development. In this study, we demonstrate that the small molecule natural product curcumin, whose medicinal properties have long been recognized in
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