Identifying New Drugs for the Treatment of Castrate Resistant Prostate Cancer: Targeting the Achilles' Heel of the Androgen Receptor.

前列腺癌是全球男性第二大常见癌症，2018年估计有130万新发病例。晚期前列腺癌患者接受激素治疗，这种药物可以阻断雄激素受体的作用。这种蛋白质存在于前列腺细胞内，与睾酮激素结合，是前列腺癌的关键驱动因素。阻断睾酮作用的药物是治疗转移性疾病的主要药物。这些药物减少睾丸激素的产生或关闭雄激素受体的活性。然而，它们的有效性因耐药性的发展而减弱，导致“去势抵抗”疾病。虽然雄激素受体在晚期疾病中仍然很重要，但目前没有新的靶向治疗方法。我们的目标是开发新的小分子抑制剂，以关闭雄激素受体的活性独立的雄激素结合状态。我们雄心勃勃，但可以实现的目标将针对受体的一部分，对功能至关重要，但不参与激素结合。将在实验室前列腺癌模型中检测特异性结合受体的候选小分子抑制剂的有效性和药物样性质，以确定其中和雄激素受体的能力。这种方法具有靶向所有已知形式的受体的优点，包括具有与去势抵抗性疾病相关的改变（突变）的受体。这种高度创新的前列腺癌治疗方法有可能显著改善晚期疾病男性的预后。

Prostate cancer is second most common cancer in men world wide, with an estimated 1.3 million new cases in 2018. Men with advanced prostate cancer are treated with hormone therapy, drugs that block the action of the androgen receptor. This protein is found inside prostate cells, binds the hormone testosterone and is a key driver of prostate cancer. Drugs which block the actions of testosterone are a mainstay for the treatment of metastatic disease. These drugs reduce the production of testosterone or switch off the activity of the androgen receptor. However, their effectiveness is blunted by the development of drug-resistance leading to 'castrate resistant' disease. While the androgen receptor remains important in advanced disease, there are currently no new targeted therapies available. We aim to develop novel small molecule inhibitors to switch off androgen receptor activity independent of the hormone-binding status. Our ambitious, but achievable aim will target a part of the receptor, essential for function, but not involved in hormone binding. The effectiveness and drug-like properties of candidate small molecule inhibitors which bind specifically to the receptor will be tested for their ability to neutralise the androgen receptor in laboratory models of prostate cancer. This approach has the advantage of targeting all known forms of the receptor, including those with alterations (mutations) associated with castrate resistant disease. This highly innovative approach to prostate cancer treatment, has the potential to significantly improve the outcome for men with advanced disease.