Application of Chemoproteomics to Drug Discovery: Identification of a Clinical Candidate Targeting Hsp90

Fadden, Patrick; Huang, Kenneth H.; Veal, James M.; Steed, Paul M.; Barabasz, Amy; Foley, Briana; Hu, Mei; Partridge, Jeffrey M.; Rice, John W.; Scott, Anisa; Dubois, Laura G.; Freed, Tiffany; Silinski, Melanie A Rehder; Barta, Thomas E.; Hughes, Philip F.; Ommen, Andy; Ma, Wei; Smith, Emilie D.; Spangenberg, Angela Woodward; Eaves, Jeron; Hanson, Gunnar J.; Hinkley, Lindsay; Jenks, Matthew; Lewis, Meredith; Otto, James C.; Pronk, Gijsbertus J.; Verleysen, Katleen; Haystead, Timothy; Hall, Steven E.

doi:10.1016/j.chembiol.2010.04.015

Cited by 76 publications

(68 citation statements)

References 41 publications

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“…The resorcinol motif is found in both the Vernalis/Novartis Phase II candidate, AUY922 and the Astex compound AT13387 [15] (34). The benzamide motif is seen in a number of the Pfizer/Serenex compounds [54] (35). 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.…”

Section: Published Hsp90 Inhibitorsmentioning

confidence: 94%

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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Section: Published Hsp90 Inhibitorsmentioning

confidence: 94%

Hsp90 Inhibitors and Drugs from Fragment and Virtual Screening

Roughley

Wright

Brough

et al. 2011

Topics in Current Chemistry

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“…1), the prodrug of SNX-2112, in mouse models of amebiasis and giardiasis. As the crystalline form of SNX-2112 was not orally bioavailable, we improved the kinetic solubility and bioavailability for oral dosing by using a glycine ester prodrug, SNX-5422, for animal studies (37,48). The advantage of using SNX-5422 in the mouse models is that full toxicological and pharmacokinetic profiles are available for this compound.…”

Section: Effect Of Hsp90 Inhibitors Against E Histolytica G Lamblimentioning

confidence: 99%

Hsp90 Inhibitors as New Leads To Target Parasitic Diarrheal Diseases

Debnath

Shahinas

Bryant

et al. 2014

Antimicrob Agents Chemother

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Entamoeba histolytica and Giardia lamblia are anaerobic protozoan parasites that cause amebiasis and giardiasis, two of the most common diarrheal diseases worldwide. Current therapy relies on metronidazole, but resistance has been reported and the drug has significant adverse effects. Therefore, it is critical to search for effective, better-tolerated antiamebic and antigiardial drugs. We synthesized several examples of a recently reported class of Hsp90 inhibitors and evaluated these compounds as potential leads for antiparasitic chemotherapy. Several of these inhibitors showed strong in vitro activity against both E. histolytica and G. lamblia trophozoites. The inhibitors were rescreened to discriminate between amebicidal and giardicidal activity and general cytotoxicity toward a mammalian cell line. No mammalian cytotoxicity was found at >100 M for 48 h for any of the inhibitors. To understand the mechanism of action, a competitive binding assay was performed using the fluorescent ATP analogue bis-ANS (4,4=-dianilino-1,1=-binaphthyl-5,5=-disulfonic acid dipotassium salt) and recombinant E. histolytica Hsp90 preincubated in both the presence and absence of Hsp90 inhibitors. There was significant reduction in fluorescence compared to the level in the control, suggesting that E. histolytica Hsp90 is a selective target. The in vivo efficacy and safety of one Hsp90 inhibitor in a mouse model of amebic colitis and giardiasis was demonstrated by significant inhibition of parasite growth at a single oral dose of 5 mg/kg of body weight/day for 7 days and 10 mg/kg/day for 3 days. Considering the results for in vitro activity and in vivo efficacy, Hsp90 inhibitors represent a promising therapeutic option for amebiasis and giardiasis.

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“…5A). Other Hsp90 inhibitors also displayed a similar defect in aggresome clearance (24,25). These data show that Hsp90 activity facilitates proteasome remodeling and aggresome clearance.…”

Section: The Intact 20s Proteasome Is Not Essential For Aggresomementioning

confidence: 62%