Hsp90 Inhibitors and Drugs from Fragment and Virtual Screening

  • Stephen Roughley
  • Lisa Wright
  • Paul Brough
  • Andrew Massey
  • Roderick E. HubbardEmail author
Part of the Topics in Current Chemistry book series (TOPCURRCHEM, volume 317)


We have previously reported the structure-based optimisation of a number of series of potent compounds progressed as clinical candidates for oncology through inhibition of the ATPase activity of the molecular chaperone, Hsp90. The starting point for these candidates was compounds discovered using a combination of structure-based hit identification methods. This chapter summarises the overall story of how these methods were applied. Virtual screening of commercially available compounds identified a number of classes of compounds. At the same time, an initial fragment screen identified 17 fragments of various classes that bound to the N-terminal domain of Hsp90 with weak (0.5–10 mM) affinity. A subsequent screen identified a total of 60 compounds. This collection of fragments and virtual screening hits were progressed in a number of ways. Although two fragments could be observed binding together in the active site, the synthetic effort required to link these fragments was judged too high. For the resorcinol class of fragments, limited library synthesis generated compounds in the 1–10 μM range. In addition, the resorcinol substructure was used to select commercially available compounds that were filtered using focussed docking in the Hsp90 active site to select further sets of compounds for assay. This identified structural motifs that were exploited during lead optimisation to generate AUY922, currently in Phase II clinical trials. In a separate campaign, features identified in the structures of fragments, evolved fragments and virtual screening hits bound to Hsp90 were combined to generate an oral series of compounds, progressed to preclinical candidates. The crystal structures were determined of many of the fragments bound to Hsp90 and provide examples of both maintenance and change of protein conformation on fragment binding. Finally, we analyse the extent to which our initial set of fragments recapitulates the key structural features of the Hsp90 inhibitors published to date.


Fragment-based drug discovery Hsp90 SAR by catalogue Structure-based drug discovery Virtual screening 



The Hsp90 project was a substantial effort which involved most members of Vernalis at one time or another. Of particular significance was the contributions of Xavier Barril, who provided the inspirational contributions in virtual screening and molecular modelling and of Ben Davis, who remains the principal driver of the development of the NMR techniques and fragment screening strategies at Vernalis. The medicinal chemistry and project leadership in the early stages was provided by Brian Dymock and Martin Drysdale successfully led the collaboration with Novartis through to the various preclinical candidates. The other members of the Hsp90 team are listed in the references [11, 17, 19, 30, 32, 33, 36, 49, 56]. The project was collaboration with the group of Paul Workman at the ICR for the discovery of AUY922 who provided much of the in vivo biology and DMPK testing for that phase of the project. The subsequent preclinical and clinical development of AUY922 and the campaigns that led to BEP800 are a collaboration with Novartis.


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Copyright information

© Springer-Verlag Berlin-Heidelberg 2011

Authors and Affiliations

  • Stephen Roughley
    • 1
  • Lisa Wright
    • 1
  • Paul Brough
    • 1
  • Andrew Massey
    • 1
  • Roderick E. Hubbard
    • 1
    • 2
    • 3
    Email author
  1. 1.Vernalis (R&D) LtdAbington, CambridgeUK
  2. 2.YSBLUniversity of YorkHeslington, YorkUK
  3. 3.HYMSUniversity of YorkHeslington, YorkUK

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