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

在英国，前列腺癌（PCa）的发病率正在上升，并首次超过了乳腺癌。据预测，六分之一的男性将在其一生中患上前列腺癌，到2020年，每年用于前列腺癌住院治疗的费用将超过3.2亿英镑。前列腺癌细胞需要雄激素（如睾酮）来增殖。传统的前列腺癌治疗包括化疗和雄激素剥夺治疗，使用化学去势和/或AR拮抗剂。然而，由于出现耐药性，这些方法对晚期致死性前列腺癌患者无效；它们也有不希望的副作用，例如阳痿、肝损伤、骨质流失、记忆力减退。这个博士项目旨在开发和生物学评价一系列新的小的，类似药物的分子，作为潜在的前列腺癌治疗先导。这些导联具有基于氮杂环[2.2.2]辛烷酰胺（ABCOA）的α -螺旋仿生支架，设计用于在共激活因子上模仿独特的FXXLF表位-蛋白质通过该表位与AR的配体结合域（LBD）内的AF2结构域具有高亲和力和特异性并增强其活性。与肽类cbi不同，我们的先导物是刚性的3D结构，有望抵抗蛋白水解，并以最小的熵成本与目标物紧密结合。这些抑制剂应使肿瘤细胞中ar依赖性转录失活，导致ar介导的致病途径选择性下调，从而为以最小副作用治疗CRPC提供新的机会，绕过当前疗法的耐药机制。

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.