PhD in Medicinal Chemistry - Identification of inhibitors of the pro-survival protein Mcl-1 as an approach to treating cancer (HOWELLU16SF)

This PhD in medicinal chemistry is designed to identify novel inhibitors of the pro-survival protein Mcl-1. The ability to evade cell death/apoptosis is a hallmark of cancer and there are vast arrays of cellular mechanisms in place which tumour cells employ to achieve this.1 One such example is Mcl-1, a member of a larger family of proteins called the Bcl-2 family. This family of proteins contains around 20 members and is responsible for controlling the apoptosis pathway.2 There are both pro- and anti-apoptotic proteins which in a healthy cell are carefully balanced to control its fate. However, in cancer high levels of the anti-apoptotic (pro-survival) proteins are often observed and not only contribute to the development of the tumour but also confer resistance to current therapies including chemotherapy and radiation treatment. In particular, elevated levels of Mcl-1 are one of the most commonly observed abnormalities in human cancer3 and are associated with the observed resistance to current therapies4,5. This PhD seeks to address this problem and identify novel small molecule inhibitors of Mcl-1. It will involve solid phase peptide synthesis as well as the biophysical and biological evaluation of the peptides synthesised.