First-in-class Selective IKKalpha Inhibitors for the Treatment of Castrate Resistant Prostate Cancer (CRPC) and Pancreatic Cancer

尽管在许多癌症的治疗方面取得了真正的进展，但仍有一些重大问题需要克服，特别是对于那些已经对治疗产生抗药性的患者，或者癌症已经扩散到原始肿瘤以外的患者。前列腺癌尤其如此，这是英国男性中最常见的癌症。在英国，每年有36000例前列腺癌新病例被诊断出来，预计这一数字在未来20年将翻一番。虽然有治疗早期前列腺癌（仍然局限于前列腺癌的癌症）的方法，但一些男性对治疗产生抗药性，癌症进展和扩散（转移）。这种类型的前列腺癌被称为去势抵抗性前列腺癌（CRPC），目前的治疗只能延长预期寿命长达9个月。因此，迫切需要治疗这种疾病的新药。我们发现了一种治疗CRPC的新方法。我们已经证明，在死亡时间较短的男性的肿瘤中，有一种名为IKKalpha的蛋白质含量很高。我们和我们的项目合作伙伴还表明，这种蛋白质参与了从早期前列腺癌到CRPC的进展。我们认为，一种阻止这种蛋白质发挥作用的药物将阻止CRPC的发展，并将预期寿命延长3年。也有证据表明，这种IKKalpha蛋白在目前无法治愈的胰腺癌中也起作用。我们是唯一一个开发出能够阻止这种蛋白质功能的化合物的团队，同时也没有阻止密切相关的蛋白质的功能（并导致不必要的副作用）。我们还证明，在实验室环境中，将我们的化合物添加到前列腺癌细胞样本中，可以减缓它们的生长并导致它们死亡。然而，这些化合物需要进一步开发，目前还不适合作为CRPC的药物。例如，它们在体内分解得太快，无法在病人身上发挥作用，而且它们也不是很溶于水，这将使它们难以施用。该项目的目的是设计具有更好性能的化合物（称为先导优化的过程）。然后，我们将能够确定我们优化的化合物是否能够阻止IKKalpha的功能，并阻止癌症在小鼠体内的生长和扩散，而不会产生不良或毒性作用。在进行人体试验之前，这一点至关重要。该项目涉及药物化学家、生物学家、临床医生和技术转移专业人员，他们作为一个团队共同努力，以实现为CRPC和胰腺癌患者提供有效新药的目标。

Despite real progress being made in the treatment of many cancers, there are still significant issues to overcome, particularly for patients who have become resistant to treatment, or where the cancer has spread beyond the original tumour. This is particularly true of prostate cancer, which is the most common cancer in men in the UK. There are 36,000 new cases of prostate cancer diagnosed every year in the UK and this figure is predicted to double over the next 20 years.Whilst there are treatments available for early-stage prostate cancer (cancer that is still confined to the prostate cancer), some men become resistant to treatment and the cancer progresses and spreads (metastasizes). This type of prostate cancer is called castrate resistant prostate cancer (CRPC) and current treatments can only extend life expectancy by up to 9 months. New medicines to treat this disease are therefore urgently needed.We have discovered a new way to treat CRPC. We have shown that there are high levels of a protein called IKKalpha in the tumours of men who had shorter time to death. We and our Project Partners have also shown that this same protein is involved in the progression from early-stage prostate cancer to CRPC. We believe that a drug which stops this protein from functioning will prevent CRPC from developing and increase life expectancy by up to 3 years. Evidence is also emerging that this IKKalpha protein also plays a role in pancreatic cancer, which is currently incurable.We are the only group to have developed compounds that stop this protein from functioning, without also stopping closely-related proteins from functioning (and resulting in unwanted side-effects).We have also demonstrated that our compounds, when added to prostate cancer cell samples in a laboratory environment, slow their growth and cause them to die. However, these compounds require further development and are not yet suitable as medicines for CRPC. For example, they are broken down in the body too quickly to exert their effects in a patient and they are also not very water-soluble, which would make them difficult to administer. The aim of this project is to design compounds with better properties (a process called lead optimisation).We will then be able to determine whether our optimised compounds stop IKKalpha from functioning and stop cancers growing and spreading in mice, without adverse or toxic effects. This is essential to demonstrate before testing in humans.This project involves medicinal chemists, biologists, clinicians and technology transfer professionals working together as a team to achieve the goal of effective new medicines for patients with CRPC and pancreatic cancer.