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

前列腺癌是全球第二常见的男性癌症，2018年估计有130万新病例。患有晚期前列腺癌的男性接受激素治疗，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，与荷尔蒙睾丸素结合，是前列腺癌的关键驱动因素。阻断睾丸素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产生而变得迟钝，这导致了对去势的抵抗性疾病。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可用。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，而不依赖于激素结合状态。我们雄心勃勃但可以实现的目标是针对受体的一部分，这是功能所必需的，但不涉及激素结合。在前列腺癌的实验室模型中，将测试与受体特异结合的候选小分子抑制剂的有效性和类似药物的特性，以确定它们中和雄激素受体的能力。这种方法的优点是靶向所有已知形式的受体，包括那些与去势抵抗疾病相关的改变(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.