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|2xdu, resolution 1.74Å ()|
|Ligands:||, , ,|
|Related:||2cdd, 1yes, 1uy9, 1byq, 2bsm, 1osf, 2wi3, 1uy8, 2bug, 2wi4, 2uwd, 2wi7, 2bt0, 1yer, 1uyg, 2ccu, 2bz5, 2ccs, 1yc3, 1uyi, 1uyf, 1uyd, 2byi, 2xdl, 2wi2, 2vci, 1uy6, 2wi1, 2vcj, 1yc4, 2c2l, 2fwz, 2xdk, 1uyk, 1uyh, 2cct, 2fwy, 1uye, 1uyl, 2wi6, 2xab, 1yc1, 1uy7, 1uyc, 1yet, 2jjc, 2byh, 2wi5, 2xdx|
Structure of HSP90 with small molecule inhibitor bound
Inhibitors of the chaperone Hsp90 are potentially useful as chemotherapeutic agents in cancer. This paper describes an application of fragment screening to Hsp90 using a combination of NMR and high throughput X-ray crystallography. The screening identified an aminopyrimidine with affinity in the high micromolar range and subsequent structure-based design allowed its optimization into a low nanomolar series with good ligand efficiency. A phenolic chemotype was also identified in fragment screening and was found to bind with affinity close to 1 mM. This fragment was optimized using structure based design into a resorcinol lead which has subnanomolar affinity for Hsp90, excellent cell potency, and good ligand efficiency. This fragment to lead campaign improved affinity for Hsp90 by over 1,000,000-fold with the addition of only six heavy atoms. The companion paper (DOI: 10.1021/jm100060b) describes how the resorcinol lead was optimized into a compound that is now in clinical trials for the treatment of cancer.
Fragment-based drug discovery applied to hsp90. Discovery of two lead series with high ligand efficiency., Murray CW, Carr MG, Callaghan O, Chessari G, Congreve M, Cowan S, Coyle JE, Downham R, Figueroa E, Frederickson M, Graham B, McMenamin R, O'Brien MA, Patel S, Phillips TR, Williams G, Woodhead AJ, Woolford AJ, J Med Chem. 2010 Aug 26;53(16):5942-55. PMID:20718493
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
[HS90A_HUMAN] Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function. 
About this Structure
- Murray CW, Carr MG, Callaghan O, Chessari G, Congreve M, Cowan S, Coyle JE, Downham R, Figueroa E, Frederickson M, Graham B, McMenamin R, O'Brien MA, Patel S, Phillips TR, Williams G, Woodhead AJ, Woolford AJ. Fragment-based drug discovery applied to hsp90. Discovery of two lead series with high ligand efficiency. J Med Chem. 2010 Aug 26;53(16):5942-55. PMID:20718493 doi:10.1021/jm100059d
- ↑ Martinez-Ruiz A, Villanueva L, Gonzalez de Orduna C, Lopez-Ferrer D, Higueras MA, Tarin C, Rodriguez-Crespo I, Vazquez J, Lamas S. S-nitrosylation of Hsp90 promotes the inhibition of its ATPase and endothelial nitric oxide synthase regulatory activities. Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8525-30. Epub 2005 Jun 3. PMID:15937123 doi:10.1073/pnas.0407294102
- ↑ Forsythe HL, Jarvis JL, Turner JW, Elmore LW, Holt SE. Stable association of hsp90 and p23, but Not hsp70, with active human telomerase. J Biol Chem. 2001 May 11;276(19):15571-4. Epub 2001 Mar 23. PMID:11274138 doi:10.1074/jbc.C100055200