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

前列腺癌(PCa)的发病率正在上升，并首次超过了英国的乳腺癌人数。据预测，每6名男性中就有1人会在一生中患上前列腺癌，到2020年，PCa的住院治疗费用将超过每年3.2亿GB。PCa细胞需要雄激素，如睾酮，才能增殖。传统的PCA治疗包括化疗和使用化学去势和/或AR拮抗剂的雄激素剥夺治疗。然而，由于耐药性的出现，这些方法对晚期致死性PCa患者无效，它们还具有不良副作用，如阳萎、肝损伤、骨丢失、记忆丧失。本博士项目旨在开发一系列新的小分子、类药物分子作为潜在的PCa治疗线索并进行生物学评价。这些先导带有一个基于氮杂双环[2.2.2]辛烷胺(ABCOA)的α-螺旋仿生支架，旨在模仿辅助激活剂上独特的FXXLF表位--通过该表位与AR配体结合区域(LBD)内的AF2结构域具有高亲和力和特异性的蛋白质，并增强其活性。与多肽CBIS不同，我们的先导是刚性的3D结构，预计会抵抗蛋白质分解，并以最小的熵成本强烈结合到他们的靶标上。这些抑制剂应该会停用肿瘤细胞中AR依赖的转录，导致AR介导的致病途径的选择性下调，从而提供新的机会，以最小的副作用治疗CRPC，绕过目前治疗的耐药机制。

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.