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Combining Hit Identification Strategies: Fragment-Based and in Silico Approaches to Orally Active 2-Aminothieno[2,3-d]pyrimidine Inhibitors of the Hsp90 Molecular Chaperone

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† Vernalis Ltd., Granta Park, Great Abington, Cambridge CB21 6GB, U.K.
‡ Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, Sutton, Surrey SM2 5NG, U.K.
§ Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland
*To whom correspondence should be addressed. Phone 44 (0)1223 895372. Fax: 44 (0)1223 895556. E-mail: [email protected]
Cite this: J. Med. Chem. 2009, 52, 15, 4794–4809
Publication Date (Web):July 17, 2009
https://doi.org/10.1021/jm900357y
Copyright © 2009 American Chemical Society
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    Abstract

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    Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential molecular therapeutic agents for the treatment of cancer. Here we describe novel 2-aminothieno[2,3-d]pyrimidine ATP competitive Hsp90 inhibitors, which were designed by combining structural elements of distinct low affinity hits generated from fragment-based and in silico screening exercises in concert with structural information from X-ray protein crystallography. Examples from this series have high affinity (IC50 = 50−100 nM) for Hsp90 as measured in a fluorescence polarization (FP) competitive binding assay and are active in human cancer cell lines where they inhibit cell proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Several examples (34a, 34d and 34i) caused tumor growth regression at well tolerated doses when administered orally in a human BT474 human breast cancer xenograft model.

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    Data relating to the PC3 human prostate cancer xenograft model for compound 34a; experimental procedures for the FP assay and synthesis of the FP assay probe and methods and parameters relating to X-ray crystallography and protein production; full chemistry experimental procedures and characterization data; methods for analytical and preparative HPLC; commercial sources for fragment and in silico screening hits; protocols relating to the 1D NMR screening of fragments; description of the process applied for the in silico screening campaign. This material is available free of charge via the Internet at http://pubs.acs.org.

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