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

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.

Pancreatic ductal adenocarcinoma or pancreatic cancer has the lowest survival rates of any cancer. According to Cancer Research UK less than 4% of patients diagnosed with the disease will survive for at least five years and this drops to less than 3% over a ten year period. More worrying though is the fact that these figures have not changed over the last 40 years despite the research efforts of many groups. In the UK alone around 8000 patients are diagnosed with pancreatic cancer every year with the majority of cases being too advanced to qualify for surgery. The prognosis for these patients is extremely poor with most given 6-12 months to live. Those patients who are eligible for surgery (usually followed by chemotherapy) have a slightly better outlook but even then the prognosis is still only 20-24 months. In addition to this, traditional chemotherapies are not generally effective against pancreatic cancer with limited responses observed.

There is, therefore, a clear and desperate need for new and improved therapeutics, with novel modes of action, to treat this horrific disease and increase long term survival rates.

The inhibition of Mcl-1 provides such an opportunity; the ultimate underlying goal of this proposal is to identify potent and selective small molecule inhibitors of Mcl-1 for the treatment of pancreatic cancer. Elevated levels of Mcl-1 are observed in pancreatic cancer and are associated with the observed resistance to current therapies such as gemcitabine. Recent studies have shown that down-regulating Mcl-1 enhances the sensitivity of human pancreatic cancer cells to gemcitabine and radiation resulting in enhanced apoptosis. These results suggest that Mcl-1 is a relevant therapeutic target for the treatment of pancreatic cancer and has a key role to play in the development of the next generation of an anti-cancer agents for the treatment of this disease. New therapeutics will clearly benefit patients diagnosed with pancreatic cancer both nationally and internationally, improving quality of life and potentially increasing survival rates. This indirectly would impact on their family and friends.In addition, if a new drug was to emerge from this research this would have a significant economic effect for the UK resulting in substantial income for the country.

In addition to the development of a novel antitumour agent, the generation of peptide-small molecule hybrids as well as small molecules may prove useful chemical biology tools. They could be used to probe the cellular pathways and mechanisms of the Mcl-1 protein which lead to its over expression in cancer. This itself may be of significant oncological importance. This may identify new targets for drug discovery programs and has the potential to lead to the generation of a new class of chemotherapeutics. Additional small molecules could be developed and optimised based on the information gathered from this researchand this could result in an expansion in the number of therapies currently available for the treatment of pancreatic cancer. This in itself may attract investment from external parties such as pharmaceutical companies.