FBMC2010MDG

Lead Optimisation of Novel Androgen Receptor Small Molecule Modulators - Improving Treatment of Prostate Cancer

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 Obiettivo del progetto (Objective)

'One of the traditional approaches for the treatment of prostate cancer is the administration of steroid-derived Androgen Receptor (AR) antagonists. These treatments show significant side effects due to their high dosing requirements. In a novel intervention approach Molecular Design Group (Trinity College Dublin), has used a variety of computational drug discovery techniques to analyse a recently identified, non-steroid AR protein binding site, termed the activation function 2 (AF2) site. The goal of this proposal is to perform lead optimisation for the development of new drugs that combat prostate cancer in a different way, circumventing the observed resistance.

The project will be implemented at Trinity College Dublin (TCD), Ireland's leading research University, supervised by Dr David Lloyd and Dr Darren Fayne, from Molecular Design Group (TCD), on the computational methodologies, Prof Mary Meegan, from the School of Pharmacy and Pharmaceuticals Studies (TCD), on the synthetic methodologies and Prof Clive Williams, from the School of Biochemistry and Immunology (TCD) on the biological assays. The responsibilities of the experienced researcher, Dr. Fernando Blanco, within the project will focus on the rational computational design and synthesis of new potential pharmaceuticals, receiving multidisciplinary training combining computational strategies, synthesis and biological assays, as well as other fundamental aspects (managing and administering of a research programme) related to strengthen the abilities of the Dr. Blanco to become a leading independent researcher in the field.

The completion of the present project is a major step in the research career of Dr. Blanco to successfully reach a position of professional maturity. In addition, the development of new small molecules to treat prostate cancer and have an impact upon translational research that will lead to clinical applications for cancer treatments is a central priority in Europe.'

Introduzione (Teaser)

A major problem of hormonal chemotherapy in prostate cancer is the development of drug resistance. An EU-funded project has been developing new alternative therapeutics for the treatment.

Descrizione progetto (Article)

Prostate cancer is one of the most prevalent cancers in the male population. Patients diagnosed with early-stage prostate cancer have excellent prognosis and can survive for many years through a chemotherapeutic anti-hormonal treatment regimen. One of the existing anti-hormonal treatments for prostate cancer involves ligand-binding pocket (LBP) antiandrogens that bind to AR in the LBP mimicking the mode of action of androgen.

Moreover, prolonged use of these drugs often results in the disease becoming hormone-refractory. The hormone-resistant cancer is frequently metastatic and almost invariably fatal. Current treatments require high dosing and show significant side-effects. The aim of this project was to develop drugs that combat prostate cancer in an alternative way.

In the present project computational rational design allowed the identification of 15 new hits by combining virtual screening, similarity and docking techniques. All these compounds have shown alternative, non-LBP, anti-androgen activity. Structural analysis of the new family of compounds (diarylhydrazides) has been performed to determine its most relevant features.

The results of this project offer an important general input for the field of rational design of new therapeutics for the treatment of drug-resistant cancer.