Click Reaction as a Tool to Combine Pharmacophores: The Case of Vismodegib

Christodoulou, Michael S.; Mori, Mattia; Pantano, Rebecca; Alfonsi, Romina; Infante, Paola; Botta, Maurizio; Damia, Giovanna; Ricci, Francesca; Sotiropoulou, Panagiota A.; Liekens, Sandra; Botta, Bruno; Passarella, Daniele

doi:10.1002/cplu.201402435

Cited by 21 publications

(19 citation statements)

References 46 publications

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“…It is worth noting that previous studies performed by our research group highlighted the reliability of computational tools in predicting the binding mode of Gli1 antagonists (i.e. the docking-based binding mode of GlaB was supported by multiple experimental evidences) [22], and Smo antagonists (the docking pose of Vismodegib was subsequently confirmed by X-ray crystallography studies) [44,50]. Therefore, these established computational protocols were used herein to dock 5 and 12 towards Gli1 zinc-finger (ZF) domain (Gli1ZF) and to dock 13 and 15 within the heptahelical bundle of Smo.…”

Section: Predicted Binding Mode Of the Most Powerful Hh Inhibitorsmentioning

confidence: 60%

“…Therefore, here we designed a smallsize focused library of isoflavones bearing different substituents in different positions of the ring B. Molecules were then tested in silico for the interaction with the heptahelical bundle of Smo or the DNA binding site of Gli1. To this aim, the computational protocols already established and validated in previous works were used [17,18,22,23,50]. Results unequivocally show that, for most of tested compounds, the O-substitution at para position of ring B is preferred for the interaction with Smo, whereas the same substitution at meta position is preferred to interact with Gli1.…”

Section: Computational Design Of Isoflavones Targeting Smo or Gli1mentioning

confidence: 98%

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Synergistic inhibition of the Hedgehog pathway by newly designed Smo and Gli antagonists bearing the isoflavone scaffold

Berardozzi

Bernardi

Infante

et al. 2018

European Journal of Medicinal Chemistry

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Aberrant activation of the Hedgehog (Hh) pathway is responsible for the onset and progression of several malignancies. Small molecules able to block the pathway at the upstream receptor Smoothened (Smo) or the downstream effector Gli1 have thus emerged recently as valuable anticancer agents. Here, we have designed, synthesized, and tested new Hh inhibitors taking advantage by the highly versatile and privileged isoflavone scaffold. The introduction of specific substitutions on the isoflavone's ring B allowed the identification of molecules targeting preferentially Smo or Gli1. Biological assays coupled with molecular modeling corroborated the design strategy, and provided new insights into the mechanism of action of these molecules. The combined administration of two different isoflavones behaving as Smo and Gli antagonists, respectively, in primary medulloblastoma (MB) cells highlighted the synergistic effects of these agents, thus paving the way to further and innovative strategies for the pharmacological inhibition of Hh signaling.

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Section: Predicted Binding Mode Of the Most Powerful Hh Inhibitorsmentioning

confidence: 60%

Section: Computational Design Of Isoflavones Targeting Smo or Gli1mentioning

confidence: 98%

Synergistic inhibition of the Hedgehog pathway by newly designed Smo and Gli antagonists bearing the isoflavone scaffold

Berardozzi

Bernardi

Infante

et al. 2018

European Journal of Medicinal Chemistry

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“…[7] Impressively,n umerous successful applications of the 1,2,3triazole as an amide bioisostere have been reported as recently reviewedb yP assarellaa nd coauthors. [2] These examples span diverse therapeutic contexts including antiviral agents, [8] chemotherapeutics, [9][10][11] antibiofilm agents, [12] antinociceptives, [13] and antipsychotics. [14] Advantageously,u se of the 1,2,3-triazole in place of the amide often affords increased biological activity, as demonstrated for viral infectivity factor (Vif)i nhibitors 1 and 2 ( Figure 2).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of 1,2,3‐Triazoles as Amide Bioisosteres In Cystic Fibrosis Transmembrane Conductance Regulator Modulators VX‐770 and VX‐809

Doiron

Ody

et al. 2019

Chemistry A European J

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The 1,2,3‐triazole has been successfully utilized as an amide bioisostere in multiple therapeutic contexts. Based on this precedent, triazole analogues derived from VX‐809 and VX‐770, prominent amide‐containing modulators of the cystic fibrosis transmembrane conductance regulator (CFTR), were synthesized and evaluated for CFTR modulation. Triazole 11, derived from VX‐809, displayed markedly reduced efficacy in F508del‐CFTR correction in cellular TECC assays in comparison to VX‐809. Surprisingly, triazole analogues derived from potentiator VX‐770 displayed no potentiation of F508del, G551D, or WT‐CFTR in cellular Ussing chamber assays. However, patch clamp analysis revealed that triazole 60 potentiates WT‐CFTR similarly to VX‐770. The efficacy of 60 in the cell‐free patch clamp experiment suggests that the loss of activity in the cellular assay could be due to the inability of VX‐770 triazole derivatives to reach the CFTR binding site. Moreover, in addition to the negative impact on biological activity, triazoles in both structural classes displayed decreased metabolic stability in human microsomes relative to the analogous amides. In contrast to the many studies that demonstrate the advantages of using the 1,2,3‐triazole, these findings highlight the negative impacts that can arise from replacement of the amide with the triazole and suggest that caution is warranted when considering use of the 1,2,3‐triazole as an amide bioisostere.

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“…In this study, following our interest in the synthesis and the identification of compounds with anticancer related bioactivities [20][21][22][23][24][25][26][27][28][29][30][31][32] , eleven chalcones were synthesized and tested against HCC cell lines and dental pulp stem cells which are reported to be hepatic progenitor properties 33 . DPSCs can proliferate and differentiate rapidly into various lineages including hepatocytes therefore they present a good model for untransformed control cells 34 .…”

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confidence: 99%

A small library of chalcones induce liver cancer cell death through Akt phosphorylation inhibition

Şahin

Christodoulou

Güzelcan

et al. 2020

Sci Rep

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Hepatocellular carcinoma (HCC) ranks as the fifth most common and the second deadliest cancer worldwide. HCC is extremely resistant to the conventional chemotherapeutics. Hence, it is vital to develop new treatment options. Chalcones were previously shown to have anticancer activities in other cancer types. In this study, 11 chalcones along with quercetin, papaverin, catechin, Sorafenib and 5FU were analyzed for their bioactivities on 6 HCC cell lines and on dental pulp stem cells (DPSC) which differentiates into hepatocytes, and is used as a model for untransformed control cells. 3 of the chalcones (1, 9 and 11) were selected for further investigation due to their high cytotoxicity against liver cancer cells and compared to the other clinically established compounds. Chalcones did not show significant bioactivity ($$\hbox {IC}_{50}>20\upmu \hbox {M}$$IC50>20μM) on dental pulp stem cells. Cell cycle analysis revealed that these 3 chalcone-molecules induced SubG1/G1 arrest. Akt protein phosphorylation was inhibited by these molecules in PTEN deficient, drug resistant, mesenchymal like Mahlavu cells leading to the activation of p21 and the inhibition of NF$$ \kappa $$κB-p65 transcription factor. Hence the chalcones induced apoptotic cell death pathway through NF$$ \kappa $$κB-p65 inhibition. On the other hand, these molecules triggered p21 dependent activation of Rb protein and thereby inhibition of cell cycle and cell growth in liver cancer cells. Involvement of PI3K/Akt pathway hyperactivation was previously described in survival of liver cancer cells as carcinogenic event. Therefore, our results indicated that these chalcones can be considered as candidates for liver cancer therapeutics particularly when PI3K/Akt pathway involved in tumor development.

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Click Reaction as a Tool to Combine Pharmacophores: The Case of Vismodegib

Cited by 21 publications

References 46 publications

Synergistic inhibition of the Hedgehog pathway by newly designed Smo and Gli antagonists bearing the isoflavone scaffold

Synergistic inhibition of the Hedgehog pathway by newly designed Smo and Gli antagonists bearing the isoflavone scaffold

Evaluation of 1,2,3‐Triazoles as Amide Bioisosteres In Cystic Fibrosis Transmembrane Conductance Regulator Modulators VX‐770 and VX‐809

A small library of chalcones induce liver cancer cell death through Akt phosphorylation inhibition

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