5-Aryl-4-(5-substituted-2,4-dihydroxyphenyl)-1,2,3-thiadiazoles as inhibitors of Hsp90 chaperone

Čikotienė, Inga; Kazlauskas, Egidijus; Matulienė, Jurgita; Michailovienė, Vilma; Torresan, Jolanta; Jachno, Jelena; Matulis, Daumantas

doi:10.1016/j.bmcl.2009.01.003

Cited by 45 publications

(39 citation statements)

References 35 publications

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“…5-Aryl-4-(5-substituted-2,4-dihydroxyphenyl)-1,2,3-thiadiazole compounds (abbreviated ICPD) were synthesized and purified as previously described [25]. Compound stocks were prepared by dissolving them in DMSO at 20 mM concentration.…”

Section: Methodsmentioning

confidence: 99%

“…For instance, new inhibitors have been designed based on benzamide [21], on 2-aminothieno[2,3-d]pyrimidine [20] and on dihydroxyphenylisoindoline [22] scaffolds. Here we study the aryl-dihydroxyphenyl-thiadiazole inhibitor [23]–[25] binding to Hsp90. Their chemical structures together with other selected Hsp90 inhibitors from the literature are shown in Figure 1.…”

Section: Introductionmentioning

confidence: 99%

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Thermodynamics of Aryl-Dihydroxyphenyl-Thiadiazole Binding to Human Hsp90

et al. 2012

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The design of specific inhibitors against the Hsp90 chaperone and other enzyme relies on the detailed and correct understanding of both the thermodynamics of inhibitor binding and the structural features of the protein-inhibitor complex. Here we present a detailed thermodynamic study of binding of aryl-dihydroxyphenyl-thiadiazole inhibitor series to recombinant human Hsp90 alpha isozyme. The inhibitors are highly potent, with the intrinsic Kd approximately equal to 1 nM as determined by isothermal titration calorimetry (ITC) and thermal shift assay (TSA). Dissection of protonation contributions yielded the intrinsic thermodynamic parameters of binding, such as enthalpy, entropy, Gibbs free energy, and the heat capacity. The differences in binding thermodynamic parameters between the series of inhibitors revealed contributions of the functional groups, thus providing insight into molecular reasons for improved or diminished binding efficiency. The inhibitor binding to Hsp90 alpha primarily depended on a large favorable enthalpic contribution combined with the smaller favorable entropic contribution, thus suggesting that their binding was both enthalpically and entropically optimized. The enthalpy-entropy compensation phenomenon was highly evident when comparing the inhibitor binding enthalpies and entropies. This study illustrates how detailed thermodynamic analysis helps to understand energetic reasons for the binding efficiency and develop more potent inhibitors that could be applied for therapeutic use as Hsp90 inhibitors.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Thermodynamics of Aryl-Dihydroxyphenyl-Thiadiazole Binding to Human Hsp90

et al. 2012

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“…53,No. 16 5951 can be added to the molecule to improve nonpotency related properties without the fear that the resulting clinical candidate lies outside druglike space.…”

Section: Articlementioning

confidence: 96%

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.

175

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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“…The present series of the 5-aryl-4-(5-substituted-2-4-dihydroxyphenyl)-1,2,3-thiadiazoles (ICPD 26, 34 and 47) were recently synthesized (Fig. 1) and shown to be effective Hsp90 inhibitors in terms of binding to Hsp90 [37]. The dissociation constant for the binding of these inhibitors to full-length Hsp90α varied from 4.8 to 39.0 nM.…”

Section: Introductionmentioning

confidence: 99%

Co-Crystalization and In Vitro Biological Characterization of 5-Aryl-4-(5-Substituted-2-4-Dihydroxyphenyl)-1,2,3-Thiadiazole Hsp90 Inhibitors

et al. 2012

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A potential therapeutic strategy for targeting cancer that has gained much interest is the inhibition of the ATP binding and ATPase activity of the molecular chaperone Hsp90. We have determined the structure of the human Hsp90α N-terminal domain in complex with a series of 5-aryl-4-(5-substituted-2-4-dihydroxyphenyl)-1,2,3-thiadiazoles. The structures provide the molecular details for the activity of these inhibitors. One of these inhibitors, ICPD 34, causes a structural change that affects a mobile loop, which adopts a conformation similar to that seen in complexes with ADP, rather than the conformation generally seen with the pyrazole/isoxazole-resorcinol class of inhibitors. Competitive binding to the Hsp90 N-terminal domain was observed in a biochemical assay, and these compounds showed antiproliferative activity and induced apoptosis in the HCT116 human colon cancer cell line. These inhibitors also caused induction of the heat shock response with the upregulation of Hsp72 and Hsp27 protein expression and the depletion of Hsp90 clients, CRAF, ERBB2 and CDK4, thus confirming that antiproliferative activity was through the inhibition of Hsp90. The presence of increased levels of the cleavage product of PARP indicated apoptosis in response to Hsp90 inhibitors. This work provides a framework for the further optimization of thiadiazole inhibitors of Hsp90. Importantly, we demonstrate that the thiadiazole inhibitors display a more limited core set of interactions relative to the clinical trial candidate NVP-AUY922, and consequently may be less susceptible to resistance derived through mutations in Hsp90.

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5-Aryl-4-(5-substituted-2,4-dihydroxyphenyl)-1,2,3-thiadiazoles as inhibitors of Hsp90 chaperone

Cited by 45 publications

References 35 publications

Thermodynamics of Aryl-Dihydroxyphenyl-Thiadiazole Binding to Human Hsp90

Thermodynamics of Aryl-Dihydroxyphenyl-Thiadiazole Binding to Human Hsp90

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

Co-Crystalization and In Vitro Biological Characterization of 5-Aryl-4-(5-Substituted-2-4-Dihydroxyphenyl)-1,2,3-Thiadiazole Hsp90 Inhibitors

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