Development and Biological Evaluation of Novel alpha-Helix Mimetic Prodrugs as Leads for Prostate Cancer Treatment

点击翻译按钮获取中文摘要

Occurrence of prostate cancer (PCa) is rising and has overtaken breast cancer numbers for the first time in the UK. It is predicted that 1 in 6 men will develop PC in their lifetime and the cost for inpatient treatment of PCa is set to exceed £320 million per year in 2020.PCa cells require androgen hormones, e.g. testosterone, to proliferate. Traditional PCa therapy involves chemotherapy and androgen-deprivation therapy using chemical castration and/or AR antagonists. However, these approaches become ineffective for patients with advanced lethal PCa due to onset of resistance; they also have undesired side-effects, e.g. impotence, liver damage, bone loss, memory loss.This PhD project is aimed at the development and biological evaluation of a new series of small, drug-like molecules as potential PCa therapeutic leads. These leads bear an azabicyclo[2.2.2]octane amide (ABCOA) based alpha-helix biomimetic scaffold designed to mimic the unique FXXLF epitope on coactivators - proteins which bind via this epitope with high affinity and specificity to the AF2 domain within the ligand binding domain (LBD) of the AR and enhance its activity. Unlike peptidic CBIs, our leads are rigid 3D structures which are anticipated to be resistant to proteolysis and to bind strongly to their target with minimum entropic cost.These inhibitors should deactivate AR-dependent transcription in tumour cells, leading to selective down-regulation of the AR-mediated disease-causing pathway, thereby offering new opportunities to treat CRPC with minimum side-effects, circumventing the resistance mechanisms of current therapies.