Structure-based design, synthesis, and evaluation of the biological activity of novel phosphoroorganic small molecule IA
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PRECLINICAL STUDIES
Structure-based design, synthesis, and evaluation of the biological activity of novel phosphoroorganic small molecule IAP antagonists Agnieszka Łupicka-Słowik 1 & Mateusz Psurski 2 & Renata Grzywa 1 & Monika Cuprych 2 & Jarosław Ciekot 2 & Waldemar Goldeman 1 & Elżbieta Wojaczyńska 3 & Jacek Wojaczyński 4 & Józef Oleksyszyn 1 & Marcin Sieńczyk 1 Received: 29 January 2020 / Accepted: 9 March 2020 # The Author(s) 2020
Summary One of the strategies employed by novel anticancer therapies is to put the process of apoptosis back on track by blocking the interaction between inhibitor of apoptosis proteins (IAPs) and caspases. The activity of caspases is modulated by the caspases themselves in a caspase/procaspase proteolytic cascade and by their interaction with IAPs. Caspases can be released from the inhibitory influence of IAPs by proapoptotic proteins such as secondary mitochondrial activator of caspases (Smac) that share an IAP binding motif (IBM). The main purpose of the present study was the design and synthesis of phosphorus-based peptidyl antagonists of IAPs that mimic the endogenous Smac protein, which blocks the interaction between IAPs and caspases. Based on the structure of the IAP antagonist and recently reported thiadiazole derivatives, we designed and evaluated the biochemical properties of a series of phosphonic peptides bearing the N-Me-Ala-Val/Chg-Pro-OH motif (Chg: cyclohexylglycine). The ability of the obtained compounds to interact with the binding groove of the X-linked inhibitor of apoptosis protein baculovirus inhibitor of apoptosis protein repeat (XIAP BIR3) domain was examined by a fluorescence polarization assay, while their potential to induce autoubiquitination followed by proteasomal degradation of cellular IAP1 was examined using the MDA-MB-231 breast cancer cell line. The highest potency against BIR3 was observed among peptides containing C-terminal phosphonic phenylalanine analogs, which displayed nanomolar Ki values. Their antiproliferative potential as well as their proapoptotic action, manifested by an increase in caspase-3 activity, was examined using various cell lines. Keywords IAP antagonist . Smac mimetic . Apoptosis . Phosphoroorganic
Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10637-020-00923-4) contains supplementary material, which is available to authorized users. * Marcin Sieńczyk [email protected] 1
Faculty of Chemistry, Department of Organic and Medicinal Chemistry, Wrocław University of Science and Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland
2
Department of Experimental Oncology, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Weigla 12, 53-114 Wrocław, Poland
3
Faculty of Chemistry, Department of Physical and Quantum Chemistry, Wrocław University of Science and Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland
4
Department of Chemistry, University of Wrocław, F. Joliot-Curie 14, 50-383 Wrocław, Poland
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