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

结合点击化学

基本信息

批准号：
EP/M006379/1
负责人：
Lesley Ann Howell
金额：
$ 12.59万
依托单位：
University of East Anglia
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2015
资助国家：
英国
起止时间：
2015 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FM006379%2F1
关键词：
Combining Click Chemistry Peptide Synthesis

项目摘要

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.

胰腺癌是英国第九大常见癌症原因，也是第五大常见癌症死亡原因。近年来，人们进行了广泛而持续的研究，重点是胰腺癌的早期发现和治疗。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被发现。对于那些早期诊断的患者，手术是可能的，但平均生存率仍然很低，五年生存率低至4%。治疗胰腺癌的一线疗法是吉西他滨，但与用于治疗癌症的大多数药物一样，它具有使人衰弱的副作用，除此之外还导致不良结局。因此，寻找能够靶向和治疗胰腺癌的具有新作用模式的新分子至关重要。细胞死亡是体内一个高度受控的过程，由一类称为Bcl-2家族的蛋白质调节。在这个家族中，有些蛋白质是促生存的，有些是促死亡的。在一个健康的细胞中，有一个控制细胞命运的谨慎平衡，只有当细胞受损时，促死亡蛋白质的水平才会上升，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，这会阻止正常的细胞死亡机制正常发挥作用。这导致肿瘤的形成以及对当前化疗和放射治疗的抵抗。Bcl-2家族的促存活成员是目前临床试验中的几种化合物的药物发现的良好验证的靶标。然而，这些化合物不靶向癌症中的关键促存活蛋白之一- Mcl-1，认为它们作为单一药物无效。高水平的Mcl-1是人类癌症中最常见的异常之一，并且与观察到的对当前疗法的抗性相关。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抗性有关。最近的一项研究表明，降低Mcl-1的水平会增强人胰腺癌细胞对吉西他滨和放射的敏感性，导致细胞死亡水平增加。因此，Mcl-1代表了一个令人兴奋的和有吸引力的目标，为下一代的癌症治疗胰腺cancer.In这个建议，我们的目标是设计一个有效的和选择性的小分子Mcl-1抑制剂的发展。我们将使用一种促死亡蛋白的部分结构作为起点，该蛋白选择性地与Mcl-1强烈结合。我们打算设计能够模拟这种促死亡蛋白并能够启动程序性细胞死亡的化合物。在这样做的过程中，我们将朝着新的化疗药物迈进，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。