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H/F PhD position Epigenetic PROTAC IBMM-IRCM Montpellier

This offer is available in the following languages:
Français - Anglais

Date Limite Candidature : mercredi 25 mai 2022

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General information

Reference : UMR5247-MARLOP-003
Workplace : MONTPELLIER
Date of publication : Wednesday, May 4, 2022
Scientific Responsible name : Marie Lopez
Type of Contract : PhD Student contract / Thesis offer
Contract Period : 36 months
Start date of the thesis : 1 October 2022
Proportion of work : Full time
Remuneration : 2 135,00 € gross monthly

Description of the thesis topic

DNA methyltransferases (DNMTs), catalysing DNA methylation, are epigenetic targets for anticancer treatment. In multiple myeloma (MM), these epigenetic writers were also identified as involved in resistance development. Current clinically used DNMT inhibitors (DNMTi) show high toxicity, due to their incorporation into DNA, and are ineffective to counter drug resistance.
In this project, we propose a novel strategy to enhance DNMTi efficacy using protein targeting chimera (PROTAC) technology, that has never been apply to DNMTs. Besides the inhibition of DNMTs, these new compounds will trigger DNMT degradation by the proteasome.
The main goals of this project are to 1) synthesise functionalised DNMTi based on active compounds identified in Lopez's group; 2) synthesise PROTAC(DNMT) using functionalised E3 ligase ligands and appropriate spacers; 3) evaluate the potency of PROTAC(DNMT) towards their targets using binding assays and 4) study the impact of these newly synthesised compound in MM patient-derived cell lines and patient primary cell lines measuring cell viability as well as methylation and expression levels for DNA methylation-regulated genes.

Work Context

Grant : 3-year fellowship from CNRS-MITI 80 PRIME 2022
Start : 1st october 2022
Collaboration : IBMM (Lopez's group) for compounds synthesis and enzyme binding assays / IGH (Moreaux's team) for compound evaluation in cell lines.

Constraints and risks

Candidates must have completed their master's degree in chemistry. Very good practical skills in multi-step organic synthesis and compound characterisation are required. The candidates must have good working knowledge and ideally experience in biochemistry/biology. The candidates should be highly motivated, inquisitive, and capable of dealing with new concepts and challenges in order to conduct this highly inter-disciplinary work. They must be able to lead their project in an independent manner as well as to work in collaboration.
Fluent level in French or English is required.

Additional Information

Candidates must have completed their master's degree in chemistry. Very good practical skills in multi-step organic synthesis and compound characterisation are required. The candidates must have good working knowledge and ideally experience in biochemistry/biology. The candidates should be highly motivated, inquisitive, and capable of dealing with new concepts and challenges in order to conduct this highly inter-disciplinary work. They must be able to lead their project in an independent manner as well as to work in collaboration.
Fluent level in French or English is required.

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