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

Beekman, Andrew M. ORCID:, O'Connell, Maria A. ORCID: and Howell, Lesley A. (2016) Identification of small-molecule inhibitors of the antiapoptotic protein myeloid cell leukaemia-1 (Mcl-1). ChemMedChem, 11 (8). 840–844. ISSN 1860-7179

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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.

Item Type: Article
Additional Information: © 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Uncontrolled Keywords: bcl-2,cancer,mcl-1,molecular modelling,protein–protein interactions,sdg 3 - good health and well-being ,/dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being
Faculty \ School: Faculty of Science > School of Pharmacy
Depositing User: Pure Connector
Date Deposited: 06 Jan 2016 15:02
Last Modified: 22 Oct 2022 00:27
DOI: 10.1002/cmdc.201500488

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