Targeting APC/C Ubiquitin E3-Ligase Activation with Pyrimidinethylcarbamate Apcin Analogues for the Treatment of Breast Cancer.

Autor: Kapanidou M; Department of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford OX3 0BP, UK., Curtis NL; Department of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford OX3 0BP, UK., Diaz-Minguez SS; Instituto de Química Orgánica, Consejo Superior de Investigaciones Científicas (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain., Agudo-Alvarez S; Instituto de Química Orgánica, Consejo Superior de Investigaciones Científicas (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain., Rus Sanchez A; Instituto de Química Orgánica, Consejo Superior de Investigaciones Científicas (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain., Mayah A; Department of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford OX3 0BP, UK., Agena R; Department of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford OX3 0BP, UK.; Department of Bioingeniería, Escuela Nacional de Ciencias Biológicas (ENCB), Instituto Politécnico Nacional, Mexico City 07738, Mexico., Brennan P; Nuffield Department of Medicine (NDM), Old Road Campus, University of Oxford, Oxford OX3 7BN, UK., Morales P; Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), Juan de la Cierva 3, 28006 Madrid, Spain., Benito-Arenas R; Instituto de Química Orgánica, Consejo Superior de Investigaciones Científicas (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain., Bastida A; Instituto de Química Orgánica, Consejo Superior de Investigaciones Científicas (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain., Bolanos-Garcia VM; Department of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Oxford OX3 0BP, UK.
Jazyk: angličtina
Zdroj: Biomolecules [Biomolecules] 2024 Nov 12; Vol. 14 (11). Date of Electronic Publication: 2024 Nov 12.
DOI: 10.3390/biom14111439
Abstrakt: Activation of the ubiquitin ligase APC/C by the protein Cdc20 is an essential requirement for proper cell division in higher organisms, including humans. APC/C is the ultimate effector of the Spindle Assembly Checkpoint (SAC), the signalling system that monitors the proper attachment of chromosomes to microtubules during cell division. Defects in this process result in genome instability and cancer. Interfering with APC/C substrate ubiquitylation in cancer cells delays mitotic exit, which induces cell death. Therefore, impairing APC/C function represents an opportunity for the treatment of cancer and malignancies associated with SAC dysregulation. In this study, we report a new class of pyrimidinethylcarbamate apcin analogues that interfere with APC/C activity in 2D and 3D breast cancer cells. The new pyrimidinethylcarbamate apcin analogues exhibited higher cytotoxicity than apcin in all breast cancer cell subtypes investigated, with much lower cytotoxicity observed in fibroblasts and RPE-1 cells. Further molecular rationalisation of apcin and its derivatives was conducted using molecular docking studies. These structural modifications selected from the in silico studies provide a rational basis for the development of more potent chemotypes to treat highly aggressive breast cancer and possibly other aggressive tumour types of diverse tissue origins.
Databáze: MEDLINE
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