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Fragment-Based Drug Discovery Applied to Hsp90. Discovery of Two Lead Series with High Ligand Efficiency
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    Fragment-Based Drug Discovery Applied to Hsp90. Discovery of Two Lead Series with High Ligand Efficiency
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    Astex Therapeutics, Ltd., 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, U.K.
    *To whom correspondence should be addressed. Phone: +44 (0)1223 226228. Fax +44 (0)1223 226201. E-mail: [email protected]
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2010, 53, 16, 5942–5955
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    https://doi.org/10.1021/jm100059d
    Published July 27, 2010
    Copyright © 2010 American Chemical Society

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    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 1000000-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.

    Copyright © 2010 American Chemical Society

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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2010, 53, 16, 5942–5955
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    https://doi.org/10.1021/jm100059d
    Published July 27, 2010
    Copyright © 2010 American Chemical Society

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