iPPI-DB: a manually curated and interactive database of small non-peptide inhibitors of protein–protein interactions

Labbé, Céline M.; Laconde, Guillaume; Kuenemann, Mélaine A.; Villoutreix, Bruno O.; Spérandio, Olivier

doi:10.1016/j.drudis.2013.05.003

Cited by 92 publications

(90 citation statements)

References 61 publications

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“…To this end, the choice of soft physicochemical thresholds like those described in the "Materials and Methods" section are inspired by several studies showing that indeed inhibitors of protein-protein interactions, and more precisely those of the Bcl-2 family, are characterized by significantly higher molecular weight and hydrophobicity, 25,26 thus standing in sharp contrast with chemistry rules such as Lipinski's RO5 and Veber's rules. 27,28 The other important step in the selection process deals with the detection of some problematic chemical moieties usually associated with toxicity or the observation of false positives or frequent hitters such as Michael acceptors or epoxides.…”

Section: Discussionmentioning

confidence: 99%

Identification of Small Inhibitory Molecules Targeting the Bfl-1 Anti-Apoptotic Protein That Alleviates Resistance to ABT-737

et al. 2014

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One approach currently being developed in anticancer drug discovery is to search for small compounds capable of occupying and blocking the hydrophobic pocket of anti-apoptotic Bcl-2 family members necessary for interacting with proapoptotic proteins. Such an approach led to the discovery of several compounds, such as ABT-737 (which interacts with Bcl-2, Bcl-xl, and Bcl-w) or the latest one, , that selectively targets Bcl-2 protein. The efficacy of those compounds is, however, limited by the expression of two other anti-apoptotic Bcl-2 members, Mcl-1 and Bfl-1. Based on the role of Bfl-1 in cancer, especially in chemoresistance associated with its overexpression in B-cell malignancies, we searched for modulators of protein-protein interaction through a high-throughput screening of a designed chemical library with relaxed drug-like properties to identify small molecules targeting Bfl-1 anti-apoptotic protein. We found two compounds that display electrophilic functions, interact with Bfl-1, inhibit Bfl-1 protective activity, and promote cell death of malignant B cells. Of particular interest, we observed a synergistic effect of those compounds with ABT-737 in Bfl-1 overexpressing lymphoma cell lines. Our results provide the basis for the development of Bfl-1 specific antagonists for antitumor therapies.

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Section: Discussionmentioning

confidence: 99%

Identification of Small Inhibitory Molecules Targeting the Bfl-1 Anti-Apoptotic Protein That Alleviates Resistance to ABT-737

et al. 2014

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“…La modulation des interactions protéine-protéine suscite donc un engouement croissant, bien que cellesci soient considérées comme des cibles particulière-ment difficiles, en raison des caractéristiques de leur interface et de leur diversité structurale [20]. Plusieurs centaines d'inhibiteurs ont été développés à ce jour pour une cinquantaine de cibles, et plusieurs bases de données leur sont consacrées [21][22][23][24][25]. L'analyse des propriétés des interfaces protéiques a conduit au développement de fonctions de score spécifiques pour évaluer leur « druggabilité » (capacité à lier une petite molécule chimique) et, ainsi, faciliter la sélection de nouvelles cibles candidates [26,27].…”

Section: Le Besoin En Chimiothèques Focaliséesunclassified

“…La validation de PPI-HitProfiler a été réalisée sur les données expérimentales de criblage de 11 cibles PPI (protein-protein interaction) différentes et un nombre cumulé de 500 000 molécules chimiques. Ce logiciel démontre, en outre, des sensibilités tout à fait comparables sur les composés d'iPPI-DB (non-peptidic inhibitor-data base) (http:// www.ippidb.cdithem.fr) [21], une base de données de modulateurs d'interactions proté ine-proté ine récemment développée et qui contient 1 650 composés pour 13 familles de cibles PPI avec leur données pharmacologiques. En effet, près de 92 % des composés d'iPPI-DB sont correctement prédits comme modulateurs d'interactions proté ine-proté ine par PPI-HitProfiler.…”

Section: Approche 2p2iunclassified

Les chimiothèques ciblant les interactions protéine-protéine

et al. 2015

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Les interactions protéine-protéine sont impliquées dans de nombreux processus cellulaires, ainsi que dans leur dysfonctionnement, ce qui en font des cibles thérapeutiques de choix. Toutefois, la conception de composés capables de moduler ce type d’interactions reste difficile et requiert la mise en place d’outils spécifiques, permettant d’accélérer les campagnes de développement de molécules bioactives et de diminuer leur coût. Les succès récents ont permis de caractériser certaines propriétés structurales et physicochimiques des interfaces protéine-protéine, ce qui a abouti à une possibilité d’inhibition de ces interactions par des petites molécules chimiques non peptidiques, ainsi qu’à la définition d’un profil caractéristique des composés chimiques associés. Dans cette revue, nous présentons le développement de collections de composés dédiées à ces cibles innovantes.

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“…However, an increasing number of small-molecule inhibitors of protein-protein interactions are now being discovered and, because many of them are drug-like, protein-protein interactions are becoming a highly promising, yet still challenging, class of therapeutic targets. [9,10] A first proof of concept of CDK inhibition by a small molecule targeting a protein-protein interaction involved the discovery of a molecule that prevents complex formation between CDK5 and its activating protein p25, thereby efficiently disrupting kinase activity. [11] Our objective here was to target protein-protein interactions that regulate some of the functions of a subset of CDKs, without being strictly necessary for their enzymatic activity.…”

Section: Introductionmentioning

confidence: 99%

Tampering with Cell Division by Using Small‐Molecule Inhibitors of CDK–CKS Protein Interactions

et al. 2015

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Cyclin-dependent kinases (CDKs) control many cellular processes and are considered important therapeutic targets. Large collections of inhibitors targeting CDK active sites have been discovered, but their use in chemical biology or drug development has been often hampered by their general lack of specificity. An alternative approach to develop more specific inhibitors is targeting protein interactions involving CDKs. CKS proteins interact with some CDKs and play important roles in cell division. We discovered two small-molecule inhibitors of CDK-CKS interactions. They bind to CDK2, do not inhibit its enzymatic activity, inhibit the proliferation of tumor cell lines, induce an increase in G1 and/or S-phase cell populations, and cause a decrease in CDK2, cyclin A, and p27(Kip1) levels. These molecules should help decipher the complex contributions of CDK-CKS complexes in the regulation of cell division, and they might present an interesting therapeutic potential.

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iPPI-DB: a manually curated and interactive database of small non-peptide inhibitors of protein–protein interactions

Cited by 92 publications

References 61 publications

Identification of Small Inhibitory Molecules Targeting the Bfl-1 Anti-Apoptotic Protein That Alleviates Resistance to ABT-737

Identification of Small Inhibitory Molecules Targeting the Bfl-1 Anti-Apoptotic Protein That Alleviates Resistance to ABT-737

Les chimiothèques ciblant les interactions protéine-protéine

Tampering with Cell Division by Using Small‐Molecule Inhibitors of CDK–CKS Protein Interactions

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