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
作者： Gabriela Chiosis , Merna N Timaul , Brian Lucas , Pamela N Munster , Fuzhong F Zheng
DOI: 10.1016/S1074-5521(01)00015-1
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摘要: Abstract Background: The Hsp90s contain a conserved pocket that binds ATP/ADP and plays an important role in the regulation of chaperone function. Occupancy this by several natural products (geldanamycin (GM) radicicol) alters Hsp90 function results degradation subset proteins (i.e. steroid receptors, Her2, Raf). We have used structural features to design small molecule inhibitor Hsp90. Results: designed PU3 competes with GM for binding relative affinity 15–20 μM. induces proteins, including manner similar GM. Furthermore, inhibits growth breast cancer cells causing retinoblastoma protein hypophosphorylation, G1 arrest differentiation. Conclusions: is representative novel class synthetic compounds proliferation cells. These reagents could provide new strategy treatment cancers.
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sci-hub.se 参考文章(26)
Mary Srethapakdi, Neal Rosen, Ranjana Tavorath, Franklin Liu, Inhibition of Hsp90 function by ansamycins causes retinoblastoma gene product-dependent G1 arrest. Cancer Research. ,vol. 60, pp. 3940- 3946 ,(2000)
Len Neckers, Theodor W. Schulte, Edward Mimnaugh, Geldanamycin as a Potential Anti-Cancer Agent: Its Molecular Target and Biochemical Activity Investigational New Drugs. ,vol. 17, pp. 361- 373 ,(1999) , 10.1023/A:1006382320697
Mary Srethapakdi, Mark M. Moasser, Neal Rosen, Pamela N. Münster, Inhibition of heat shock protein 90 function by ansamycins causes the morphological and functional differentiation of breast cancer cells. Cancer Research. ,vol. 61, pp. 2945- 2952 ,(2001)
Chrisostomos Prodromou, S. Mark Roe, Peter W. Piper, Laurence H. Pearl, A molecular clamp in the crystal structure of the N-terminal domain of the yeast Hsp90 chaperone Nature Structural & Molecular Biology. ,vol. 4, pp. 477- 482 ,(1997) , 10.1038/NSB0697-477
Michael Nüsse, Wolfgang Beisker, Christine Hoffmann, Attila Tarnok, Flow cytometric analysis of G1‐ and G2/M‐phase subpopulations in mammalian cell nuclei using side scatter and DNA content measurements Cytometry. ,vol. 11, pp. 813- 821 ,(1990) , 10.1002/CYTO.990110707
Theodor W. Schulte, Shiro Akinaga, Shiro Soga, William Sullivan, Bridget Stensgard, David Toft, Leonard M. Neckers, Antibiotic radicicol binds to the N-terminal domain of Hsp90 and shares important biologic activities with geldanamycin. Cell Stress & Chaperones. ,vol. 3, pp. 100- 108 ,(1998) , 10.1379/1466-1268(1998)003<0100:ARBTTN>2.3.CO;2
David O Toft, Recent Advances in the Study of hsp90 Structure and Mechanism of Action. Trends in Endocrinology and Metabolism. ,vol. 9, pp. 238- 243 ,(1998) , 10.1016/S1043-2760(98)00060-5
William B. Pratt, David O. Toft, Steroid receptor interactions with heat shock protein and immunophilin chaperones Endocrine Reviews. ,vol. 18, pp. 306- 360 ,(1997) , 10.1210/EDRV.18.3.0303
S. Mark Roe, Chrisostomos Prodromou, Ronan O'Brien, John E. Ladbury, Peter W. Piper, Laurence H. Pearl, Structural Basis for Inhibition of the Hsp90 Molecular Chaperone by the Antitumor Antibiotics Radicicol and Geldanamycin Journal of Medicinal Chemistry. ,vol. 42, pp. 260- 266 ,(1999) , 10.1021/JM980403Y
Brian Lucas, Neal Rosen, Gabriela Chiosis, Facile synthesis of a library of 9-alkyl-8-benzyl-9H-purin-6-ylamine derivatives. ACS Combinatorial Science. ,vol. 3, pp. 518- 520 ,(2001) , 10.1021/CC010017T