Combining Click Chemistry & Peptide Synthesis to Generate Novel Inhibitors of the Anti-Apoptotic Protein Mcl-1 for the Treatment of Pancreatic Cancer

胰腺癌是英国第九大最常见的癌症原因，也是第五大癌症死亡原因。近年来，人们对胰腺癌的早期发现和治疗进行了广泛而持续的研究。然而，尽管如此，患者的预后并不好，大多数病例在疾病的晚期才被发现。对于那些早期确诊的患者，手术是可能的，但平均存活率仍然很低，患者存活5年的比例低至4%。治疗胰腺癌的一线疗法是吉西他滨，但像大多数用于治疗癌症的药物一样，它有使人衰弱的副作用，除此之外，还会导致不良结果。因此，寻找具有新的作用模式的新分子来靶向和治疗胰腺癌是至关重要的。细胞死亡在体内是一个高度受控的过程，由一类被称为Bcl-2家族的蛋白质调节。在这个家族中，一些蛋白质促进生存，一些促进死亡。在一个健康的细胞中，有一种微妙的平衡控制着细胞的命运，只有当细胞被破坏时，促死蛋白的水平才会上升，导致细胞死亡。然而，在各种人类癌症（包括胰腺癌）中，促生存蛋白的水平升高，这阻止了正常细胞死亡机制的正常运作。这导致了肿瘤的形成以及对目前的化疗和放疗的抵抗。Bcl-2家族的促生存成员是目前处于临床试验中的几种化合物的药物发现的良好验证靶点。然而，这些化合物并不针对癌症中关键的促生存蛋白之一Mcl-1，认为它们作为单一药物是无效的。高水平的Mcl-1是人类癌症中最常观察到的异常之一，并与观察到的对当前治疗的耐药性有关。例如，Mcl-1过表达与观察到的对紫杉醇和长春新碱以及吉西他滨的耐药性有关。最近的一项研究表明，降低Mcl-1的水平会增强人类胰腺癌细胞对吉西他滨和辐射的敏感性，导致细胞死亡水平增加。因此，Mcl-1代表了下一代胰腺癌治疗药物开发的一个令人兴奋和有吸引力的目标。在这个提议中，我们的目标是设计一种有效的、选择性的Mcl-1小分子抑制剂。我们将使用一种前死亡蛋白的部分结构作为起点，它选择性地和强结合Mcl-1。我们打算设计能够模拟这种促死亡蛋白的化合物，并能够启动程序性细胞死亡。在此过程中，我们将朝着新的化疗药物前进，这些药物在胰腺癌中具有增强的活性，可用于治疗这种可怕的疾病。

Pancreatic cancer is the 9th most common cause of cancer in the UK and the 5th most common cause of cancer deaths. In recent years there has been an extensive and continuous research effort which has focussed on the early detection and treatment of pancreatic cancer. However, despite this, the prognosis for patients is not good with most cases being detected in the advanced stages of the disease. For those patients who are diagnosed early, surgery is possible but the average survival rate is still poor with the percentage of patients who survive the disease for five years as low as 4%. The first line therapy for the treatment of pancreatic cancer is gemcitabine but, like most drugs used for the treatment of cancer, it has debilitating side effects and in addition to this also leads to a poor outcome. The search for new molecules with novel modes of action that can target and treat pancreatic cancer is therefore of utmost importance. Cell death is a highly controlled process in the body that is regulated by a class of proteins called the Bcl-2 family. Within this family some proteins are pro-survival and some are pro-death. In a healthy cell there is a careful balance that controls the fate of the cell and only when the cell is damaged do the levels of the pro-death proteins rise resulting in cell death. However, in a variety of human cancers (including pancreatic cancer) there are elevated levels of the pro-survival proteins which prevents the normal cell death mechanisms from functioning correctly. This leads to the formation of a tumour as well as resistance to current chemotherapy and radiation treatment. The pro-survival members of the Bcl-2 family are well validated targets for drug discovery with several compounds currently in clinical trials. However, these compounds do not target one of the key pro-survival proteins in cancer - Mcl-1, deeming them ineffective as single agents. High levels of Mcl-1 are one of the most commonly observed abnormalities in human cancer and are associated with the observed resistance to current therapies. For example, Mcl-1 overexpression is linked to resistance observed against paclitaxel and vincristine as well as gemcitabine. A recent study has shown that reducing the levels of Mcl-1 enhances the sensitivity of human pancreatic cancer cells to gemcitabine and radiation, resulting in increased levels of cell death. Mcl-1 therefore represents an exciting and attractive target for the development of the next generation of cancer therapeutics for the treatment of pancreatic cancer.In this proposal, we aim to design a potent and selective small molecule inhibitor of Mcl-1. We will use part of the structure of one of the pro-death proteins, which binds selectively and strongly to Mcl-1, as a starting point. We intend to design compounds that will be able to mimic this pro-death protein and be able to initiate programmed cell death. In doing this, we will move forward towards new chemotherapeutic agents that have enhanced activity in pancreatic cancer and can be used to treat this dreadful disease.