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中第二大常见癌症，2018年估计有130万新病例。晚期前列腺癌患者采用激素疗法，即阻断雄激素受体活动的药物。这种蛋白存在于前列腺细胞内，与睾丸激素结合，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。这些药物会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，从而导致“去势抵抗”疾病。虽然雄激素受体在晚期疾病中仍然很重要，但目前还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，以关闭雄激素受体活性独立于激素结合状态。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，但不涉及激素结合。候选小分子抑制剂与受体特异性结合的有效性和药物样特性将在前列腺癌的实验室模型中测试其中和雄激素受体的能力。这种方法的优点是可以靶向所有已知形式的受体，包括那些与去势抗性疾病相关的改变（突变）。这种高度创新的前列腺癌治疗方法，有可能显著改善晚期前列腺癌患者的预后。

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.