Discovery and Design of Novel HSP90 Inhibitors Using Multiple Fragment‐based Design Strategies

Huth, Jeffrey R.; Park, Chang; Petros, Andrew M.; Kunzer, Aaron; Wendt, Michael; Wang, Xilu; Lynch, Christopher L.; Mack, J.; Swift, Kerry M.; Judge, Russell A.; Chen, Jun; Richardson, Paul L.; Jin, Sha; Tahir, Stephen K.; Matayoshi, Edward D.; Dorwin, Sarah A.; Ladror, Uri S.; Severin, Jean M.; Walter, Karl A.; Bartley, Diane; Fesik, Stephen W.; Elmore, Steven W.; Hajduk, Philip J.

doi:10.1111/j.1747-0285.2007.00535.x

Cited by 110 publications

(98 citation statements)

References 27 publications

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“…The conformational movement has previously been observed with larger compounds in Hsp90 47 and has also been reported with fragments, although no X-ray structures of fragments have been disclosed. 48,49 Other conformations for this mobile region were also observed during our Hsp90 project, but this one is notable because it opens up a large lipophilic pocket that can be exploited in drug design. Fragment 4 makes only lipophilic interactions with the induced pocket formed by the side chains of Leu107, Phe 138, Tyr139, and Trp162.…”

Section: Resultsmentioning

confidence: 76%

Fragment-Based Drug Discovery Applied to Hsp90. Discovery of Two Lead Series with High Ligand Efficiency

Murray¹,

Carr²,

Callaghan³

et al. 2010

J. Med. Chem.

174

162

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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 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.

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Section: Resultsmentioning

confidence: 76%

Fragment-Based Drug Discovery Applied to Hsp90. Discovery of Two Lead Series with High Ligand Efficiency

Murray¹,

Carr²,

Callaghan³

et al. 2010

J. Med. Chem.

174

162

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“…Finally, there have been two published reports of successful fragment linking approaches which have combined a core, purine replacement scaffold with a compound that binds in the methoxy-benzene second site pocket. Both examples [from Evotec [47] and from Abbott [42] (36)] have generated extended compounds where the affinity is greater than an individual fragment, but not the full additivity of energy expected from optimal combination. To date, there has been no report of either of these compounds progressing further in optimisation or clinical trials.…”

Section: Published Hsp90 Inhibitorsmentioning

confidence: 98%

“…The Abbott group has reported series of such projects in which linking (sometimes requiring quite considerable chemical effort) has generated advanced lead compounds (e.g. [42][43][44][45]). However, there are only a few other reports of successful linking campaigns, with two examples being [46] and [47], probably because of the challenges.…”

Section: Fragment Evolution: Linking Fragmentsmentioning

confidence: 99%

Hsp90 Inhibitors and Drugs from Fragment and Virtual Screening

Roughley

Wright

Brough

et al. 2011

Topics in Current Chemistry

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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.

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“…This also appears to be true for screening by X-ray crystallography. While there have been several reports of ternary complexes observed via crystallographic screening, these appear to be rare and optimization via linking difficult [24,25].…”

Section: Evolution At Abbottmentioning

confidence: 93%

Fragment-based lead discovery: challenges and opportunities

Sun

Petros

Hajduk

2011

J Comput Aided Mol Des

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Fragment-based lead discovery has undergone remarkable changes over the last 15 years. During this time, the pharmaceutical industry has changed dramatically as well, and continued evolution of the industry is assured. These changes present many challenges but also several opportunities for executing fragment-based drug design. This article will explore some of the more significant changes in the industry and how they may affect future discovery efforts related to fragment-based initiatives.

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Discovery and Design of Novel HSP90 Inhibitors Using Multiple Fragment‐based Design Strategies

Cited by 110 publications

References 27 publications

Fragment-Based Drug Discovery Applied to Hsp90. Discovery of Two Lead Series with High Ligand Efficiency

Fragment-Based Drug Discovery Applied to Hsp90. Discovery of Two Lead Series with High Ligand Efficiency

Hsp90 Inhibitors and Drugs from Fragment and Virtual Screening

Fragment-based lead discovery: challenges and opportunities

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