Zoe Maylin

Zoe Maylin


About

My research project

Publications

Zoe R Maylin, Radu CB Nicolescu, Hardev Pandha, Mohammad Asim (2021) Breaking androgen receptor addiction of prostate cancer by targeting different functional domains in the treatment of advanced disease
In the last decade, treatment for castration-resistant prostate cancer has changed markedly, impacting symptom control and longevity for patients. However, a large proportion of cases progress despite androgen deprivation therapy and chemotherapy, while still being fit enough for several more lines of treatment. Overstimulation of the androgen receptor (AR) activity is the main driver of this cancer. Targeting biological functions of the AR or its co-regulators has proven very effective in this disease and led to the development of several highly effective drugs targeting the AR signalling axis. Drugs such as enzalutamide demonstrated that the improvement in anti-tumour efficacy is closely correlated with an affinity for the AR and its activity and have established the paradigm that AR remains activity in aggressive disease. However, as importantly, key insights into mechanisms of resistance are guiding the development of the next generation of AR-targeted drugs. This review outlines the historical development of these highly specific agents, their mechanism of action in the context of defective AR activity, and explores the potential for the upcoming next-generation AR inhibitors (ARI) for prostate cancer by targeting the alternative domains of AR, rather than by the conventional ligand-binding domain approach. There is huge potential in these approaches to develop new drugs with high clinical activity and further improve the outlook for patients.
RCB Nicolescu, ZR Maylin, FJ Pérez-Arealesa, J Iegrea, HS. Pandha, M Asim and DR Spring (2022) Hybrid androgen receptor inhibitors outperform enzalutamide and EPI-001 in in vitro models of prostate cancer drug resistance
Abstract: Androgen receptor targeted therapies for prostate cancer have serious limitations in advanced stages of the disease. While resistance to the FDA-approved enzalutamide is extensively documented, novel therapies based on epichlorohydrin scaffolds (EPI) are currently in clinical trials, but display suboptimal pharmacokinetics. Herein, we report the synthesis and biological characterisation of a novel class of compounds designed through covalently linking enzalutamide and EPI-001 through various triazole based linkers. The compounds display a 100-fold improvement in the cell killing potency towards C4-2b PC cells compared to the gold standards of therapy, enzalutamide and EPI-001. The most promising compounds were proven to exhibit their toxicity exclusively through AR mediated pathways. This work sets the basis for the first class of hybrid AR inhibitors which successfully combine two drug moieties – EPI-001 and enzalutamide – into the same molecule.