Targeting wide-range oncogenic transformation via PU24FCl, a specific inhibitor of tumor Hsp90.
Agents that inhibit Hsp90 function hold significant promise in cancer therapy. Here we present PU24FCl, a representative of the first class of designed Hsp90 inhibitors. By specifically and potently inhibiting tumor Hsp90, PU24FCl exhibits wide-ranging anti-cancer activities that occur at similar doses in all tested tumor types. Normal cells are 10- to 50-fold more resistant to these effects. Its Hsp90 inhibition results in multiple anti-tumor-specific effects, such as degradation of Hsp90-client proteins involved in cell growth, survival, and specific transformation, inhibition of cancer cell growth, delay of cell cycle progression, induction of morphological and functional changes, and apoptosis. In concordance with its higher affinity for tumor Hsp90, in vivo PU24FCl accumulates in tumors while being rapidly cleared from normal tissue. Concentrations achieved in vivo in tumors lead to single-agent anti-tumor activity at non-toxic doses.
Vilenchik
Maria
M
Program in Cell Biology and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021 USA.
Solit
David
D
Basso
Andrea
A
Huezo
Henri
H
Lucas
Brian
B
He
Huazhong
H
Rosen
Neal
N
Spampinato
Claudia
C
Modrich
Paul
P
Chiosis
Gabriela
G
D000225:Adenine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000840:Anisoles / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy*; D013997:Time Factors
C494602:2-fluoro-8-((2-chloro-3,4,5,-trimethoxyphenyl)methyl)-9-pentyladenine; D000840:Anisoles; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D000225:Adenine