Identification of small-molecule inhibitors of the antiapoptotic protein myeloid cell leukaemia-1 (Mcl-1)

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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.
Original languageEnglish
Pages (from-to)840–844
Number of pages5
Issue number8
Early online date30 Nov 2015
Publication statusPublished - 19 Apr 2016


  • Bcl-2
  • cancer
  • Mcl-1
  • molecular modelling
  • protein–protein interactions

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