Towards a New Frontier in Autophagy Inhibition: The Development of a Novel Class of Chemical Probes and Identification of Their Associated Biological Target

Informations projet

inhibitAUTO

N° de convention de subvention: 794259

DOI

10.3030/794259

Projet clôturé le 31 Août 2018

Date de signature de la CE 19 Février 2018

Date de début 1 Mars 2018

Date de fin 29 Février 2020

Financé au titre de

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coût total

€ 171 460,80

Contribution de l’UE

€ 171 460,80

Coordonné par

MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Germany

Periodic Reporting for period 1 - inhibitAUTO (Towards a New Frontier in Autophagy Inhibition: The Development of a Novel Class of ChemicalProbes and Identification of Their Associated Biological Target)

Période du rapport: 2018-03-01 au 2020-02-29

Résumé du contexte et des objectifs généraux du projet

The dysregulation of the lysosomal degradation (autophagy) pathway has been implicated in several degenerative conditions including cancer. The development of efficient measures to control autophagy therefore potentially offers a desperately needed pathway through which cancer progression may be regulated. Around a quarter of deaths in Europe are currently attributed to cancer, and it is estimated that 90% of these deaths are caused by metastases. Inhibition of autophagy has recently been shown to block cell migration and prevent metastases in tumour models.

This action aims to discover a novel class of autophagy inhibitors and newly develop chemical probes that can identify their protein targets, and dissect their biological mode of action in relation to autophagy modulation.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

An enabling synthetic method was developed and applied to prepare a collection of compounds that fused an sp3-rich ring system with an sp2-rich ring system (~50 compounds). These compounds are structurally related to a series of autophagy inhibitors (“oxautins”) that were previously identified by the Waldmann group. The biological activity of the compounds was investigated in a range of cell-based phenotypic assays (including assays that monitor glucose uptake, hedgehog signalling, and autophagy pathways) and they were found to inhibit autophagy with sub-micromolar activity. To investigate the structure activity relationship, a further 15 analogues of the lead compound were prepared, enabling the identification of a new lead compound with nanomolar potency.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

A new class of autophagy inhibitors with considerably higher potency than the originally developed compound series (“oxautins”) has been realised (nM activity for the new lead compound, where only uM activity was exhibited by the previous lead compound series, oxautins). Studies will now investigate the minimum pharmacophore required for activity, as well as probe the mode of action through chemical biology techniques, in order to try to identify the molecular target(s) associated with the inhibitory activity observed. It is anticipated that the findings of this project will broadly have value towards increasing the understanding of unknown biological mechanisms underlying degenerative diseases such as cancer, which, ultimately, may aid the development of effective new treatments in future.

Fluorescence microscopy images for the cell based autophagy assay.