PhD offer - Development of SUMOylation inhibitors

The research will be carried out at the Max Mousseron Institute of Biomolecules (IBMM) in the "Amino acids, heterocycles, peptides and proteins" team, which is made up of about twenty permanent staff members whose activity is dedicated to the development of bioactive compounds and chemical tools for biology. More information is available online: https://ibmmpeptide.com/
The work is carried out in collaboration with the team of G. Bossis (Institute of Molecular Genetics of Montpellier, IGMM) also present on the CNRS campus of Montpellier, route de Mende.

SUMOylation, a post-translational modification of the ubiquitin family, plays a critical role in the response of Acute Myeloid Leukemias (AMLs) to chemotherapies (Bossis et al, Cell Reports, 2014) and differentiation therapies (Baik et al, Cancer Research, 2018). Deregulations of SUMOylation are associated with AML resistance to chemotherapies (Gâtel et al, Life Science Alliance, 2020). Thus, targeting SUMOylation is a therapeutic avenue for the treatment of AML.
In this context, a consortium of teams from different disciplines: chemistry (IBMM, Montpellier), biology (IGMM, Montpellier), structural biology (CRM2, Nancy), in collaboration with the University Hospital of Montpellier, has undertaken to identify new SUMOylation inhibitors and to determine their therapeutic potential in AML. Our approach consists in synthesizing pseudopeptides mimicking a key SUMOylation enzyme to inhibit its interaction with a protein partner. We have synthesized more than 40 peptide sequences that have been tested for their ability to inhibit the interaction between the two enzymes (in collaboration with the team of M. Lois, Barcelona) and the SUMOylation reaction in vitro. This allowed the identification of 3 "hit" peptides. Sequence modifications of these peptides are in progress to optimize their efficiency (hit to lead approach).
In parallel, we are developing PROTACs (proteolysis-targeting chimeras). These are bi-functional molecules, one part interacting with the target and the other with an E3-ubiquitin ligase. The interaction of PROTAC with its target leads to its ubiquitylation and degradation by the proteasome.
The candidate will be a key element in the development and synthesis of new generation molecules and must be an excellent organicist and master the synthesis of complex peptides on solid support (SPPS). His/her profile should be resolutely oriented towards research at the interface between chemistry and biology. Skills in the analysis of 3D protein structures and in molecular dynamics would be an advantage.