Responsabile Scientifico

• TRON Gian Cesare (DSF)

Partecipanti al progetto

• APRILE Silvio (DSF)
• GROLLA Ambra (DSF)
• MANFREDI Marcello (DiMET)

Titolo del progetto

• Old dog, new tricks. Inhibiting HDACs using isonitriles. Novel epigenetic drugs against triple negative breast cancer

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-29095

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

• €333.000,00

Sustainable Development Goals - Agenda 2030

Keyword

• Drug discovery and/or development
• Chemistry
• Organic compounds
• Histone modifications
• Triple negative breast ca

Stato del progetto

• Approvato

Abstract

• Background Histone deacetylase (HDAC) enzymes control the acetylation grade of histones and of several intracellular proteins. They catalyze the removal of the acetyl group from lysines on histones. This favours their tight binding to DNA, blocking the genes transcription. HDACs are overexpressed in cancer, downregulating the expression of tumor suppressor genes. It has been demonstrated how the inhibition of HDACs by small organic molecules in cancer cells has a profound impact on some crucial biological events such as cell cycle regulation, differentiation and apoptosis. Five HDAC inhibitors have been approved for cutaneous/peripheral T-cell lymphoma and a dozen are in clinical trials for other malignancies. Most of the existing HDAC inhibitors contain an hydroxamic acid group as chelating moiety for the zinc ion of HDACs. Unfortunately, this functional group is responsible for unfavorable pharmacodynamic and pharmacokinetic properties. Hypothesis The identification of a novel coordinating group would be of great value for a new generation of HDAC inhibitors, devoid of the problems associated with the presence of the hydroxamic acid moiety. To this end, our idea is to use the neglected isonitrile group, which is a biocompatible, strong metal coordinating agent (stable in plasma and metabolically resistant in specific frameworks) and a putative acetyl lysine isostere. This replacement should originate a generation of HDAC inhibitors with improved pharmacodynamic and pharmacokinetic properties characterized by in vivo stability, lack of mutagenicity and improved selectivity compared with hydroxamate based inhibitors. Aims The goal of this project is to develop a novel generation of HDACi, replacing the hydroxamic acid with the neutral isonitrile. Such a replacement will be carried out on clinical and pre-clinical inhibitors containing the hydroxamate warhead as well as on de-novo molecular designed compounds. They will be validated for their pharmacodynamic properties both on enzymes and in vitro cancer cell lines and for their ADMET properties. The first in class compounds will be evaluated in vivo. Experimental Design The goals will be achieved in a multidisciplinary context, characterized by the interplay between medicinal chemists and pharmacologists following this experimental design: 1. Synthesis of existing HDACi replacing the hydroxamate group with an isonitrile. 2. De novo drug design of novel putative HDACi with an isonitrile as warhead 3. The synthesized compounds will be tested in enzymatic and cellular assays to evaluate their inhibitory activity towards the HDAC6 and/or SIRT2 isoforms 4. ADME properties will be evaluated for the most promising compounds (plasmatic and hepatic metabolism, permeability, aqueous solubility) 5. The final candidates will be evaluated in vivo against TNBC bearing mice. Expected Results The use of the isonitrile as warhead in HDAC6 inhibitors is an underexplored opportunity to generate a smart generation of HDAC inhibitors with improved properties. We expect that this approach will give access to potent and selective reversible or irreversible HDAC inhibitors. Impact On Cancer The identification of selective, biorthogonal covalent or non-covalent inhibitors of HDAC6 is still a lacking area in the epigenetic field. The discovery of such compounds will fill in a blank area, giving to the community new molecules both as pharmacological tools and candidates for cancer therapy.