Identification of Small-Molecule Inhibitors of the Antiapoptotic Protein Myeloid Cell Leukaemia-1 (Mcl-1)

Abstract

Protein-protein interactions (PPIs) control many cellular processes in cancer and tumour growth. Of significant interest is the role PPIs play in regulating apoptosis. The overexpression of the antiapoptosis regulating Bcl-2 family of proteins is commonly observed in several cancers, leading to resistance towards both radiation and chemotherapies. From this family, myeloid cell leukemia-1 (Mcl-1) has proven the most difficult to target, and one of the leading causes of treatment resistance. Exploiting the selective PPI between the apoptosis-regulating protein Noxa and Mcl-1, utilising a fluorescence polarization assay, we have identified four small molecules with the ability to modulate Mcl-1. The identified compounds were computationally modelled and docked against the Mcl-1 binding interface to obtain structural information about their binding sites allowing for future analogue design. When examined for their activity towards pancreatic cell lines that overexpress Mcl-1 (MiaPaCa-2 and BxPC-3), the identified compounds demonstrated growth inhibition, suggesting effective Mcl-1 modulation.