Optimization of TRPV6 Calcium Channel Inhibitors Using a 3D Ligand‐Based Virtual Screening Method

Simonin, Céline; Awale, Mahendra; Brand, Michael; Deursen, Ruud van; Schwartz, J.; Fine, Michael; Kovács, Gergely; Häfliger, Pascal; Gyimesi, Gergely; Sithampari, Abilashan; Charles, Roch‐Philippe; Hediger, Matthias A.; Reymond, Jean‐Louis

doi:10.1002/ange.201507320

Cited by 11 publications

(23 citation statements)

References 40 publications

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“…We recently reported the identification of CIS22a (Fig. 5 a) as the first potent and selective inhibitor of TRPV6, a transmembrane calcium channel overexpressed in breast and prostate cancer [ 46 ]. We tested the polypharmacology of this inhibitor for 24 out of 44 targets present in the “safety screen” panel of Cerep Pvt.…”

Section: Resultsmentioning

confidence: 99%

“…PPB searches through 2.7 M ligand-target interactions extracted from ChEMBL 21 and generates a list of predicted targets, each linked to the lists of known actives used for the prediction. PPB validation is presented for 670 drugs of known polypharmacology as well as in a predictive application of off-targets for a recently reported inhibitor of transient receptor potential vanilloid 6 (TRPV6) [ 46 ]. PPB is freely accessible at www.gdb.unibe.ch and works on computers, tablets and phones.…”

Section: Introductionmentioning

confidence: 99%

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The polypharmacology browser: a web-based multi-fingerprint target prediction tool using ChEMBL bioactivity data

Awale

Reymond

2017

J Cheminform

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Background Several web-based tools have been reported recently which predict the possible targets of a small molecule by similarity to compounds of known bioactivity using molecular fingerprints (fps), however predictions in each case rely on similarities computed from only one or two fps. Considering that structural similarity and therefore the predicted targets strongly depend on the method used for comparison, it would be highly desirable to predict targets using a broader set of fps simultaneously.ResultsHerein, we present the polypharmacology browser (PPB), a web-based platform which predicts possible targets for small molecules by searching for nearest neighbors using ten different fps describing composition, substructures, molecular shape and pharmacophores. PPB searches through 4613 groups of at least 10 same target annotated bioactive molecules from ChEMBL and returns a list of predicted targets ranked by consensus voting scheme and p value. A validation study across 670 drugs with up to 20 targets showed that combining the predictions from all 10 fps gives the best results, with on average 50% of the known targets of a drug being correctly predicted with a hit rate of 25%. Furthermore, when profiling a new inhibitor of the calcium channel TRPV6 against 24 targets taken from a safety screen panel, we observed inhibition in 5 out of 5 targets predicted by PPB and in 7 out of 18 targets not predicted by PPB. The rate of correct (5/12) and incorrect (0/12) predictions for this compound by PPB was comparable to that of other web-based prediction tools.ConclusionPPB offers a versatile platform for target prediction based on multi-fingerprint comparisons, and is freely accessible at www.gdb.unibe.ch as a valuable support for drug discovery.Graphical abstract. Electronic supplementary materialThe online version of this article (doi:10.1186/s13321-017-0199-x) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The polypharmacology browser: a web-based multi-fingerprint target prediction tool using ChEMBL bioactivity data

Awale

Reymond

2017

J Cheminform

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“…To search for new angiogenesis inhibitors, we selected 201 compounds from commercial catalogsd ue to their 3D-shape and pharmacophore similarity to four knownr eceptor tyrosine kinase inhibitors (Supporting Information Figure S1a) using our previously reported algorithm xLOS, [11] an approachw hich had served us well previously to discover AuroraAkinase inhibitors. [12] We then screened our focused library for angiogenesis inhibition activity in ac o-culture assay in which kinase inhibitors are detected because they disrupt cellular network formation.…”

Section: Resultsmentioning

confidence: 99%

“…[13] Our focusedl ibrary contained 33 triazines relatedt o1.T he screening data with these triazines indicatedt hat activity required am ethyl substituent on the furan ring and a para substituento nt he aniline ring (TableS1). To furthere lucidate the SAR of this compound series,w es ynthesized seventeen additional triazines (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)w ith this substitution pattern. Following known procedures, [14] condensation of p-substituted anilines with N-cyanoguanidine gave phenyl biguanide intermediates 19-29,w hich were condensed with methyl chloroacetate to form chloromethyl triazine intermediates 30-40.T hese intermediates were finally coupled with o-hydroxya cetophenone and analogues to form the final products (Scheme 1).…”

Section: Resultsmentioning

confidence: 99%

Identifying Lysophosphatidic Acid Acyltransferase β (LPAAT‐β) as the Target of a Nanomolar Angiogenesis Inhibitor from a Phenotypic Screen Using the Polypharmacology Browser PPB2

et al. 2018

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By screening a focused library of kinase inhibitor analogues in a phenotypic co‐culture assay for angiogenesis inhibition, we identified an aminotriazine that acts as a cytostatic nanomolar inhibitor. However, this aminotriazine was found to be completely inactive in a whole‐kinome profiling assay. To decipher its mechanism of action, we used the online target prediction tool PPB2 (http://ppb2.gdb.tools), which suggested lysophosphatidic acid acyltransferase β (LPAAT‐β) as a possible target for this aminotriazine as well as several analogues identified by structure–activity relationship profiling. LPAAT‐β inhibition (IC50 ≈15 nm) was confirmed in a biochemical assay and by its effects on cell proliferation in comparison with a known LPAAT‐β inhibitor. These experiments illustrate the value of target‐prediction tools to guide target identification for phenotypic screening hits and significantly expand the rather limited pharmacology of LPAAT‐β inhibitors.

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“…35,48 . Due to the involvement of TRPV6 channels in cancer cell proliferation 46,49 and its overexpression in numerous cancer models, attempts have been made to virtually screen TRPV6's Ca 2+ channel inhibitors 50 . The crystal structure for TRPV6 was recently solved and enabled us to model the potential Tv1/TRPV6 interaction (Fig.…”

Section: Discussionmentioning

confidence: 99%

Antitumor effects of Tv1 venom peptide in liver cancer

Holford

Ogunwobi

Huaman

et al. 2019

Preprint

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A strategy for treating the most common type of liver cancer, hepatocellular carcinoma (HCC) applies a targeted therapy using venom peptides that are selective for ion channels and transporters overexpressed in tumor cells. Here, we report selective anti-HCC properties of Tv1, a venom peptide from the predatory marine terebrid snail, Terebra variegata. Tv1 was applied in vitro to liver cancer cells and administered in vivo to allograft tumor mouse models. Tv1 inhibited the proliferation of murine HCC cells via calcium dependent apoptosis resulting from down-regulation of the cyclooxygenase-2 (COX-2) pathway. Additionally, tumor sizes were significantly reduced in Tv1-treated syngeneic tumor-bearing mice. Tv1's mechanism of action involves binding to specific transient receptor potential (TRP) cation channels that are overexpressed in HCC cell models. Our findings demonstrate the unique potential of venom peptides to function as tumor specific ligands in the quest for targeted cancer therapies.

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Optimization of TRPV6 Calcium Channel Inhibitors Using a 3D Ligand‐Based Virtual Screening Method

Abstract: Herein, we report the discovery of the first potent and selective inhibitor of TRPV6, ac alcium channel overexpressed in breast and prostate cancer,a nd its use to test the effect of blocking TRPV6-mediated Ca 2+

Cited by 11 publications

References 40 publications

The polypharmacology browser: a web-based multi-fingerprint target prediction tool using ChEMBL bioactivity data

The polypharmacology browser: a web-based multi-fingerprint target prediction tool using ChEMBL bioactivity data

Identifying Lysophosphatidic Acid Acyltransferase β (LPAAT‐β) as the Target of a Nanomolar Angiogenesis Inhibitor from a Phenotypic Screen Using the Polypharmacology Browser PPB2

Antitumor effects of Tv1 venom peptide in liver cancer

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