Responsabile Scientifico

• PIRALI Tracey (DSF)

Partecipanti al progetto

• DEL GROSSO Erika (DSF)
• FALLARINI Silvia (DSF)
• MASSAROTTI Alberto (DSF)
• MIGGIANO Riccardo (DSF)
• DI MARTINO Rita Maria Concetta (DSF)

Titolo del progetto

• Leveraging new chemical modalities for reprogramming IDO1 half-life in cancer immunotherapy

Ente finanziatore

• 
  AIRC - Fondazione AIRC per la Ricerca sul Cancro

Programma di finanziamento

• AIRC2023

Bando di riferimento

• IG - Investigator Grant 2023

Anno di presentazione del progetto

• 2023

Anno di approvazione del progetto

• 2023

Project ID / numero contratto

• IG-2023 ID-29452

Durata del progetto

• 63 mesi

Inizio del progetto

• 02/01/2024

Fine del progetto

• 31/03/2029

Ente capofila

• UNIUPO - Universita Degli Studi del Università del Piemonte Orientale "Amedeo Avogadro"

Progetto approvato - Contributo unità di ricerca del Dipartimento

• €482.000,00

Sustainable Development Goals - Agenda 2030

Keyword

• Drug discovery and/or development
• Small molecule inhibitors
• Immunotherapy
• Protein degradation
• Preclinical studies

Stato del progetto

• Approvato

Abstract

• Background One of the key proteins in promoting immune escape and limiting the clinical benefit of cancer immunotherapy is IDO1. Many catalytic inhibitors have been developed over the years. Yet, the disappointing results have raised the hypothesis that some features of IDO1 biology might have been overlooked. IDO1 is a far more complex protein than first thought, shaping up to be a moonlighting protein and acting as a signaltransducing immune regulator. Through specific docking sites IDO1 interacts with molecular partners, resulting in the upregulation of its gene expression or in its degradation by the proteasomal system. It is also able to self-regulate its catalytically active form (holo-IDO1), shifting toward a heme-free conformation (apo- IDO1). Hypothesis Our hypothesis is that the acceleration of IDO1 turnover and the consequent reduction of IDO1 protein level, which will impact on both the catalytic and signalling activity, is the most effective modality for targeting IDO1. Such innovative approach would likely overcome the limitations observed with classical inhibitors. Aims The aim is the identification of a cluster of: i) molecules able to module the signalling activities of IDO1 and to (a) reduce the interaction of IDO1 with SHPs (and, in turn, reduce the sustained expression of the protein) or (b) potentiate the interaction of IDO1 with SOCS3 (and, in turn, increase the proteasomal degradation of the protein); (ii) PROTACs (that induce the formation of a ternary complex IDO1-PROTAC-E3 ligase and the degradation of IDO1 by UPS) targeting as E3 ligases VHL, CRBN and NEDD4, overexpressed in pancreatic ductal adenocarcinoma (PDAC), and as protein of interest IDO1 (and TDO). Experimental Design The project is based on the tight interplay among structural biology information, biophysical studies and highthroughput chemical synthesis, as well as virtual and real screening processes, that will work in synergy to conceive a well-informed decision tree to select the most promising candidates. These will be evaluated for their PK and PD profile in wild-type mice and for their efficacy and safety in models of PDAC. Expected Results A set of compounds, compatible with in vivo administration, will be identified that modulate signalling activities or cause chemical knock down of both catalytic and nonenzymatic activities. They will be instrumental to: (i) understand which is the most effective strategy for targeting IDO1; (ii) investigate the still poorly understood role of the IDO-1 apo-form and decipher its moonlighting properties; (iii) investigate if it is possible to achieve tumor-specificity by targeting E3 ligases overexpressed in PDAC (e.g. NEDD4). While the discovery of such modulators is currently based on serendipity, we also aim at shading light on the binding modality of these molecules, offering elements that will drive their rational design. Impact On Cancer The identified compounds will point out a new direction for IDO1 drug discovery and lay the basis for therapeutics with a clinical potential. While our candidates will be initially tested in PDAC, the approach has the great potential to challenge different cancer settings in which IDO1 plays a role, opening novel therapeutic opportunities in cancer immunotherapy.