Small-molecule targeting of heat shock protein 90 chaperone function: rational identification of a new anticancer lead.
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. Here we present a combined structure- and dynamics-based computational design strategy, taking the flexibility of the receptor and of a lead peptidic antagonist into account explicitly, to identify the nonpeptidic small molecule 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) as a structurally novel inhibitor of Hsp90. The compound is selected to bind the Hsp90 N-terminal domain, mimicking the chemical and conformational properties of the recently described peptidic antagonist of the survivin-Hsp90 complex, shepherdin [Plescia et al. Cancer Cell 2005, 7, 457-468]. Experimental tests show that AICAR binds the Hsp90 N-domain, destabilizes multiple Hsp90 client proteins in vivo, including survivin, and exhibits antiproliferative and proapoptotic activity in multiple tumor cell lines, while not affecting proliferation of normal human fibroblasts. We propose that AICAR represents a viable lead for further development of anticancer drugs with wide therapeutic opportunities.
Meli
Massimiliano
M
Istituto di Chimica del Riconoscimento Molecolare, Consiglio Nazionale delle Ricerche, Via Mario Bianco 9, 20131 Milan, Italy.
Pennati
Marzia
M
Curto
Maria
M
Daidone
Maria Grazia
MG
Plescia
Janet
J
Toba
Sam
S
Altieri
Dario C
DC
Zaffaroni
Nadia
N
Colombo
Giorgio
G
D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D020650:Combinatorial Chemistry Techniques; D003198:Computer Simulation; D015195:Drug Design; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D012265:Ribonucleotides / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D007004:Hypoglycemic Agents; D010446:Peptide Fragments; D011994:Recombinant Proteins; D012265:Ribonucleotides; C503112:shepherdin; D000620:Aminoimidazole Carboxamide; C031143:AICA ribonucleotide