Proteins belonging to the BCL-2 family are key regulators of apoptosis.1 The subtle interplay between pro-survival and pro-apoptotic members of this family dictates the fate of cells. Upon intra- and extra-cellular stress signals, the BCL-2 proteins mediate apoptotic signals leading to cytochrome c release, caspase activation and final destruction of essential cellular components. Deregulation of the balance between these proteins leads to a wide range of diseases: for example, up-regulation of the pro-survival proteins is a key step towards tumour formation and progression and is also linked to resistance to current anti-cancer treatments.2 Targeting the BCL-2 proteins with small molecules represents a highly attractive new paradigm in anti-cancer therapy. 3
Key discoveries at the Walter and Eliza Hall Institute have contributed to a better understanding of the role played by the BCL-2 proteins in the apoptotic pathway. By developing molecular probes targeting members of this family, we aim to investigate the role of pro-survival proteins in cancer progression using chemical biology strategies.4 Within the BCL-2 family of protein, MCL-1 has remained a considerable challenge for medicinal chemists with only one publication reporting clear evidence of binding through X-ray crystallography.5 With the aim to reproduce the interaction between the selective peptide ligand NOXA-BH3 and MCL-1, we designed and prepared a series of peptidomimetics based on a benzoylurea scaffold. We present the efficient synthesis of these compounds as well as their affinity for MCL-1 as measured by two distinct binding assays. These compounds exhibit potencies in the micromolar range, and therefore represent potential starting point for further investigations towards potent MCL-1 inhibitors.