Natural iminosugar (+)-lentiginosine inhibits ATPase and chaperone activity of hsp90.
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 cell viability. The relevance of Hsp90 as a therapeutic target for numerous diseases states has prompted the identification and optimization of novel Hsp90 inhibitors as an emerging therapeutic strategy. We performed a screening aimed to identify novel Hsp90 inhibitors among several natural compounds and we focused on the iminosugar (+)-lentiginosine, a natural amyloglucosidases inhibitor, for its peculiar bioactivity profile. Characterization of Hsp90 inhibition was performed using a panel of chemical and biological approaches, including limited proteolysis, biochemical and cellular assays. Our result suggested that the middle domain of Hsp90, as opposed to its ATP-binding pocket, is a promising binding site for new classes of Hsp90 inhibitors with multi-target anti-cancer potential.
Dipartimento di Scienze Farmaceutiche e Biomediche, Università di Salerno, Fisciano, Italy.
Fabrizio
F
Dal Piaz
Antonio
A
Vassallo
Maria Giovanna
MG
Chini
Franca M
FM
Cordero
Francesca
F
Cardona
Claudio
C
Pisano
Giuseppe
G
Bifulco
Nunziatina
N
De Tommasi
Alberto
A
Brandi
D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000470:Alkaloids / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D050111:Imino Sugars / Q000494:pharmacology*; D015394:Molecular Structure; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D020349:Surface Plasmon Resonance; D013816:Thermodynamics
D000470:Alkaloids; D018841:HSP90 Heat-Shock Proteins; D050111:Imino Sugars; C063984:lentiginosine; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases