Hsp90 Inhibitors and Drugs from Fragment and Virtual Screening

Abstract

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.

Computational Methods in Drug Discovery

“…SB-vHTS has been used successfully in identifying novel and potent hits in several drug discovery campaigns Lu et al, 2006;Zhao et al, 2006;Ruiz et al, 2008;Triballeau et al, 2008;Li et al, 2009;Budzik et al, 2010;Izuhara et al, 2010;Simmons et al, 2010;Roughley et al, 2012). We discuss two examples in which SB-vHTS played pivotal role in discovery of lead compounds.…”

“…Hsp90 is a molecular chaperone that modulates the activity of multiple oncogenic processes, which makes it an important therapeutic target for oncology. Roughley et al (2012) virtually screened 0.7 million compounds from rCat (Baurin et al, 2004) with Hsp90 to identify leads that led to the development of potent inhibitors of Hsp90. Crystal structures of Hsp90 bound to previously known inhibitors were used in the docking-based virtual screen.…”

Fragment Based Drug Design: From Experimental to Computational Approaches

“…Their efforts led to the development of a compound with comparable potency to approved drugs that target FPPS. Researchers at Vernalis [119] also used "SAR by catalog" approach to search compound containing resorcinol substructure in their inhouse database as a means to identify lead compounds against Hsp90. One of the hit compounds that initially showed IC 50 of 300nM was optimized by medicinal chemistry modification into a 9nM potency compound.…”

Exploring the Trypanosoma brucei Hsp83 Potential as a Target for Structure Guided Drug Design

“…As was previously described, the nucleotide-binding site can be divided into the adenosine and the phosphate binding pockets [25]. All the inhibitors described here occupy both pockets but differ in how they expand or modify these binding cavities [60], [61], [62]. All of the inhibitor scaffolds recapitulate the adenosine mode of binding to the chaperone (Fig.…”