Description of the thesis topic

The DDR team at IPBS has recently discovered, through a multidisciplinary approach carried out in collaboration with teams from LCC and SPCMIB, the cytotoxic mechanism of action of a large family of natural and bioinspired small molecules. These molecules act as prodrugs bioactivated into cytotoxic compounds by HSD17B11, a human enzyme of the Short-Chain Dehydrogenases/Reductases (SDRs) super-family (eLife 2022). In order to exploit the therapeutic potential of this mechanism against small-cell lung cancer, we have developed within the framework of this consortium new synthetic approaches enabling the generation of more active, selective and stable derivatives in biological media and in animals (J Med Chem 2023; patent 2021). Moreover, we have shown that this mechanism is generalizable, i.e. that new prodrugs selectively bioactivated by other SDRs can be developed.
We are currently the only team in the world to exploit SDR bioactivation for therapeutic approaches. The thesis project we are proposing aims to capitalize on our advances to develop the first prodrugs bioactivated by 2 SDRs with highly restricted expression in normal tissues but overexpressed in cancers with a poor prognosis, in particular liver and pancreatic cancers. We have already identified hit compounds for both enzymes. A PhD chemist will exploit a new modular synthesis approach developed by the LCC and SPCMIB (manuscript in preparation) to generate a panel of analogues with the aim of increasing activity, selectivity and stability in animals. A PhD student biologist (this offer) will test these analogues, validating their mechanism of action and anticancer activity in mouse models. This work will enable us to develop new targeted cancer therapies, while reinforcing Toulouse's leading position in these new therapeutic molecules.

Work Context

The PhD program is based at the Institut de Pharmacologie et de Biologie Structurale (IPBS) in Toulouse, in the “Deciphering & drugging DNA Repair” team headed by Sébastien Britton. The candidate will be under the supervision of Sébastien Britton (IPBS) and Yves Génisson (SPCMIB). This contract is part of the research program funded by the TIRIS Scaling-Up Science project “SDR-to-Lead”, aimed at developing new prodrugs against aggressive cancers.

Constraints and risks

BSL2 labwork.