A small molecule designed to bind to the adenine nucleotide pocket of Hsp90 causes Her2 degradation and the growth arrest and differentiation of breast cancer cells.
BACKGROUND
The Hsp90s contain a conserved pocket that binds ATP/ADP and plays an important role in the regulation of chaperone function. Occupancy of this pocket by several natural products (geldanamycin (GM) and radicicol) alters Hsp90 function and results in the degradation of a subset of proteins (i.e. steroid receptors, Her2, Raf). We have used the structural features of this pocket to design a small molecule inhibitor of Hsp90.


RESULTS
The designed small molecule PU3 competes with GM for Hsp90 binding with a relative affinity of 15-20 microM. PU3 induces degradation of proteins, including Her2, in a manner similar to GM. Furthermore, PU3 inhibits the growth of breast cancer cells causing retinoblastoma protein hypophosphorylation, G1 arrest and differentiation.


CONCLUSIONS
PU3 is representative of a novel class of synthetic compounds that binds to Hsp90 and inhibits the proliferation of cancer cells. These reagents could provide a new strategy for the treatment of cancers.
Chiosis
G
G
Program in Cell Biology and Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021, USA. chiosisg@mskmail.mskcc.org
Timaul
M N
MN
Lucas
B
B
Munster
P N
PN
Zheng
F F
FF
Sepp-Lorenzino
L
L
Rosen
N
N
D000227:Adenine Nucleotides / Q000378:metabolism*; D016227:Benzoquinones; D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D015195:Drug Design; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D047029:Lactams, Macrocyclic; D011485:Protein Binding; D011809:Quinones / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000187:drug effects* / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000227:Adenine Nucleotides; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011809:Quinones; D018719:Erb-b2 Receptor Tyrosine Kinases; C001277:geldanamycin