Projet ANR-15-CE18-0023 – PPI-Chem : Développement de stratégies innovantes ciblant la modulation spécifique de complexes protéine-proteine
Programme : Innovation médicale, nanotechnologies, médecine régénérative, thérapies et vaccins innovants (DS0412) 2015
Année de financement : 2015
Coordinateur du projet : Monsieur Xavier Morelli (Centre National de la Recherche Scientifique délégation Provence et Corse _ [Centre de Recherche en Cancérologie de Marseille])
Partenaires : Laboratoire public; PME; Laboratoire public; Laboratoire public; Laboratoire public; Laboratoire public
Montant : 524598.0 euros
Date de début : 2015
Durée : 36 mois
Résumé : Protein-protein interactions (PPI) play a major role in most biological processes and they are involved in various cell disorders, leading to numerous diseases. As a consequence, PPI have emerged as a new class of very promising therapeutic targets despite being considered as challenging targets mainly due to the nature of the interface that did not evolve to interact with small molecule compounds unlike enzymes or receptors, for example. One of the most effective way to start a drug discovery program targeting PPI, especially when no structural data is available for the target, is high throughput screening (HTS). This strategy relies on the screening of a collection of medium or large size collection of compounds. In addition to the structural and biophysical complexity of the interfacial features of transiently formed complexes, the major hurdle in the field concern the nature of small molecule compounds that are used to search for PPI modulators. The poor hit rate success in drug discovery campaigns is often due to a choice of screening libraries that are not adapted to PPI’s chemical space. There is therefore a major need to develop innovative chemical libraries dedicated to PPI to be shared with the scientific community. Data concerning both PPI targets and their small molecule inhibitors has resulted in the development of dedicated structural databases; two of them being setup and maintained by members of this consortium. Detailed analyses of the physicochemical properties of the small molecule compounds in the respective databases resulted in the definition of a characteristic profile of PPI disruptors that was used to develop dedicated algorithms and select ‘PPI inhibitor-like’ compounds within large collection of compounds. 
In this proposal, we offer to build a PPI-oriented chemical library, compatible with drug discovery constraints that will be made public and available to the scientific community as a powerful tool for discovering new biological probes and early hits for the development of potential therapeutic drugs. We will first optimize our current algorithms and tools by taking into account recent results from the screening of our PPI-focused chemical library of 1,664 compounds that was used as a proof of concept as well as current data from our respective databases dedicated to PPI. Some important issues such as solubility of the compounds, physicochemical properties, interference with bioassays, drug-likeness or pharmacokinetics properties will also be considered. This work will result in optimized and standardized protocols that will be applied to various vendors compound collections to build a diverse chemical library of approximately 10,000 compounds that will be purchased, plated and stored. Compounds in the PPI-targeting library will be evaluated for their cytotoxicity on three human cell lines. The focused library will then be evaluated against 10 structurally diverse PPI targets using cell-based or in vitro assays such as homogeneous time-resolved fluorescence (HTRF) and fluorescence polarization technologies (FP). Primary hits will be validated using dose-response bioassays and IC50 will be measured for the best compounds.
This study will first result in improved strategies to select ‘PPI inhibitor-like’ compounds from large collections of small molecules. A validated PPI-oriented chemical library of approximately 10,000 small molecule compounds will be made available through MTA to academic laboratories, screening platforms, biotech’s and pharmaceutical industries. Several chemical probes will be developed during the validation phase of this proposal on 10 biologically important targets. As a direct consequence of this proposal, the large distribution of the library will also stimulate the development of other chemical probes that will provide innovative tools to study biological processes involving protein-protein interactions. Some of these probes may guide new therapeutic developments.