Design of Small Molecule Inhibitors of the Pro-Survival Protein Mcl-1 (360G-Wellcome-211564_Z_18_Z)

Apoptosis is a highly conserved and controlled process, with the Bcl-2 family of proteins playing an important role as key regulators. The family consists of both pro- and anti-apoptotic proteins and there is a careful balance within a cell controlling its fate. High levels of the anti-apoptotic proteins are often observed in cancer and not only contribute to the development of the tumour but also confer resistance to current therapies including chemotherapy and radiation treatment. In particular over-expression of myeloid cell leukemia-1 (Mcl-1) is one of the most common forms of genetic abnormality in cancer. In addition Mcl-1 has been shown to be essential for some tumours survival, resulting in a genetic vulnerability of the cancer cells which can be exploited by the design of Mcl-1 specific inhibitors. As a single agent, an inhibitor would target tumours that rely on Mcl-1 for survival and in combination with other therapies it is expected to overcome Mcl-1 mediated resistance. We have recently identified a small molecule capable of modulating the interaction between Mcl-1/Noxa. In this proposal we now seek to improve the binding affinity and selectivity of the compound through synthesising a small library of analogues.