Brain-permeable IRE1 inhibitors for adjuvant therapy in glioblastoma: from hit- to-lead (ADDITINIB)

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Brain-permeable IRE1 inhibitors for adjuvant therapy in glioblastoma: from hit- to-lead (ADDITINIB)

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Job description

Offer DescriptionCall for expression of interest descriptionThe is a highly prestigious renowned EU-funded scheme. It offers talented scientists a unique chance to set up 2-year research and training projects with the support of a supervising team. Besides providing an attractive grant, it represents a major opportunity to boost the career of promising researchers.Research laboratories in Brittany are thus looking for excellent postdoctoral researchers with an international profile to write a persuasive proposal to apply for a Marie S. Curie Postdoctoral Fellowship grant in 2024 (deadline of the EU call set on 11 September 2024). The topic and research team presented below have been identified in this regard.Main Research FieldChemistry (CHE)Research sub- field(s)Life Sciences (LIF)Keywordsmedicinal chemistry, synthesis, kinase, inhibitors, glioblastomaResearch project description1. Context.ADDITINIB is a medicinal chemistry project involving chemists from the ISCR CNRS UMR 6226 & biologists from the Inserm U1242 (both located in Rennes) devoted to the conception of novel drug candidates to fight glioblastoma (GB). GB is an aggressive primary brain tumor yielding a median survival of ~15 months post-diagnosis, mainly as a consequence of current treatments failure. The biologists’ team previously identified the Inositol Requiring Enzyme (IRE1) kinase as an eligible pharmacological target demonstrating both its pivotal role in GB development and the effectiveness of its inhibition in GB mouse models when given in combination with the standard therapies.[1]However, current available IRE1 inhibitors are are prone to off-target effects and none is pharmacologically suitable for brain studies, thereby justifying the research of new, brain-permeable, series of compounds.2. Status of the team’s work and hypothesis.Following an in-silico campaign, a novel class of IRE1 kinase-domain inhibitors displaying brain permeability properties and being effective in GB mouse models was identified as the starting point of a medicinal chemistry program.[2]Then, a first level of computed-supported pharmacomodulation was conducted leading to the generation of a library of 80 compounds.[3,4]The in vitro evaluation of these first-generation analogs allowed the identification of improved hits active in the nanomolar range (
15 fold the initial hit). However, one of the current limitations to rationally develop this series and explore in depth the structure-activity relationships (SAR) is the absence of co-complex crystal structures to define the precise binding mode in the IRE1 kinase domain.3. Objectives.The ADDITINIB postdoctoral project is part of an already well-established research program and will contribute in particular to: * Provide critical information on the interactions of our previously developed hit compounds in complex with IRE1 cytosolic domain using X-ray protein crystallographyand their effect on IRE1 kinase and RNase activities through the use of biophysical assays.

• Develop lead-like compounds with improved potency, kinase selectivity and ADMET properties.
• Characterize the effect of these novel BBB-permeable IRE1 inhibitors in cellular and animal models of GB administered alone or in combination with the standard of care.

To achieve these goals, a collaboration with Dr P. Maisonneuve (IECB, Bordeaux, France) has been initiated, yielding apo IRE1 crystals under optimization before X-ray analysis. Inhibitors will then be tested in soaking or co-crystallization experiments. The structure(s) obtained will then permit building of an in-house QSAR model. A secondment at the IECB in Bordeaux will give to the Postdoctoral fellow the opportunity to be trained and involved in the protein crystallization process. Besides, additional biophysical assays such as displacement assay measured by microscale thermophoresis (MST) or fluorescent polarization (FP), as well as kinase ATP conversion (ADPGlo) will be carried out to determine the Kd values and quantify the kinase inhibition, respectively.References. * Trends in Cancer, 2020, 6, 1018. 10.1016/j.trecan.2020.07.006

• iScience, 2023, 106687. 10.1016/j.isci.2023.106687
• WO2023131677, 2023.
• Patent application N°EP23306135.7, 2023.

SupervisorsThe Postdoctoral Fellow will be supervised by Pr. François-Hugues PORÉE & Dr Eric Chevet.Supervisor 1: F.-H. Porée obtained a PharmD from Université Paris Sud (now Paris Saclay) in 2001. He then completed his formation with a PhD in organic chemistry at Cergy Paris Université and a Post-doctoral fellow in the laboratory of Pr Fürstner (Mülheim/Ruhr). During 15 years, FHP was Assistant Professor in Pharmacognosy at the Faculty of Pharmacy of Paris (Université Paris Cité), before being appointed in 2019 Full Professor in Medicinal Chemistry at the Faculty of Pharmacy of Rennes (Université de Rennes – ISCR UMR CNRS 6226). His interests covered the field of bioactive compounds displaying anticancer or antimicrobial activities with an emphasis for the synthesis of natural products series.Google scholar .Supervisor 2: Dr. Eric Chevet is a 1st class Research Director at Inserm and heads the Inserm U1242 unit (90 people – Rennes) and the PROSAC team in this unit. He is a world expert in Endoplasmic Reticulum stress signaling and ER homeostasis. EC has obtained an Avenir team in 2007 and since then has coordinated many grants (INCa, FRM) and has partnered in large consortia (EUH2020, ERANET). EC has authored more than 210 articles (H-index: 70;
33k cites – GoogleScholar), he holds 7 patents and is a founder of Thabor Therapeutics (https:// EC is editor at the FEBS Journal and editor in chief for Traffic. The PROSAC team aims at elucidating the molecular mechanisms that control IRE1 physiological functions and at developing novel IRE1 modulators to control those functions.Google scholar .Department/researchChemistry : The Institut des Sciences Chimiques de Rennes (ISCR) is a joint Research Department (UMR : Unité Mixte de Recherche) associating the CNRS, the Université de Rennes, the Ecole Nationale Supérieure de Chimie de Rennes (ENSCR) and the Institut National des Sciences Appliquées de Rennes (INSA de Rennes). The ISCR’s ambition is to conduct high-level research in the design, synthesis and characterization of molecules and functional materials for applications in health, materials, optics and energy. The Institute brings more than 280 permanent people organized in eight research teams and possesses all the facilities to carry out state-of-the-art research. The Institute attractiveness led to the obtention of seven EU and several national grants.Website:Biology: The INSERM U1242 laboratory is a translational research structure bringing together biologists, chemists and clinicians to better understand oncogenesis in brain and gynecological cancers. By associating biologists working on cancer stress signaling pathways, chemists developing molecular tools and cancer clinicians, the laboratory aims at deciphering how tumor cells cope with stresses to resist to death and how they could be sensitized to treatments. The candidate will benefit from an exciting and multidisciplinary scientific environment with on-site access to cutting-edge facilities in biochemistry, biophysics, molecular biology, cell biology and structural biology.Website:In particular, the ADDITINIB project is part of a medicinal project involving Pr F.-H. Porée (ISCR Team Corint) and Dr E. Chevet (Inserm U1242) and is supported by La Ligue contre la Cancer (regional funding) and Inserm-ITMO Cancer Aviesan (national funding 2023-2026). The consortium also includes a collaboration with Pr L. Eriksson (Gothenburg University, Sweden) for molecular modeling studies.Website: – inhibitors-adjuvant-therapy-glioblastomaLocationFaculty of Pharmacy of Rennes (Villejean Campus)Suggestion for interdisciplinary / intersectoral secondments and placementsOpportunity to do a secondment at IECB (Bordeaux, France) under the guidance of Dr Pierre Maisonneuve to support the protein and co-complex ligand-protein crystals production.RequirementsResearch Field Chemistry Education Level PhD or equivalentSkills/Qualifications

• Specific Skill Requirements: organic chemistry and/or medicinal chemistry
• Additional Knowledge (optional): protein crystallisation, biophysical analysis, molecular modelling
• Required Languages: English
• Publications: at least 1 per year since the PhD in 1st author

The candidate will evolve in an interdisciplinary environment at the interface between chemistry and biology. A participation to the redaction of calls (national, European level) would be envisaged.Languages ENGLISH Level ExcellentAdditional InformationEligibility criteriaAcademic qualification: By 11 September 2024, applicants must be in possession ofa doctoral degree, defined as a successfully defended doctoral thesis, even if the doctoral degree has yet to be awarded.Research experience: Applicants must have a maximum of 8 years full-time equivalentexperience in research, measured from the date applicants were in possession of a doctoral degree. Years of experience outside research and career breaks (e.g. due to parental leave), will not be considered.Nationality & Mobility rules: Applicants can be of any nationality but must not haveresided more than 12 months in France in the 36 months immediately prior to the MSCA-PF call deadline on 11 September 2024.Selection processWe encourage all motivated and eligible postdoctoral researchers to send their expressions of interest through the EU Survey application form ( ), before 5th of May 2024. Your application shall include:

• a CV specifying: (i) the exact dates for each position and its location (country) and (ii) a list of publications;

• a cover letter including a research outline (up to 2 pages) identifying the research synergies with the project supervisor(s) and proposed research topics described above.

Deadline for sending an expression of interest5th May 2024Selection of the most promising application(s)May – June 2024Writing the MSCA-PF proposal with the support of the above-mentioned supervisor(s)June – September 2024MSCA-PF 2024 call deadline11th September 2024Publication of the MSCA-PF evaluation resultsFebruary 2025Start of the MSCA-PF project (if funded)May 2025 (at the earliest)Website for additional job detailsWork Location(s)Number of offers available 1 Company/Institute Institut des Sciences Chimiques de Rennes – UMR CNRS 6226 Country France City Rennes Postal Code 35042 Street 263 avenue Général Leclerc GeofieldWhere to apply WebsiteContact CityRennes WebsiteStreet263 avenue Général Leclerc Postal Code35042 E-Mail[email protected]STATUS: EXPIRED

Expected salary

Location

Rennes, Ille-et-Vilaine

Job date

Sun, 31 Mar 2024 07:48:32 GMT

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