Abstract
SummaryOne 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.
Highlights
Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Apoptosis, a process of programmed cell death, is a fundamental mechanism under precise homeostatic control
As shown in previous studies, the methyl group of the Ala residue fits into the hydrophobic pocket formed by the Leu131, Trp134 and Glu143 side chains of ML-inhibitor of apoptosis proteins (IAPs), and because of steric limitations, it is difficult to replace with more complex substituents [38]
The amino group of Ala interacts with the carboxylates of Asp138 and Glu143 in ML-IAP, Glu314 in X-linked inhibitor of apoptosis protein (XIAP) and Asp320 and Glu325 in cIAP1 [38, 43, 44]
Summary
A process of programmed cell death, is a fundamental mechanism under precise homeostatic control. It assures a delicate balance between cell survival and death, which is crucial for embryogenesis as well as for sustaining a constant number of mature cells while preventing the spread of infectious diseases. Suppression of apoptosis is utilized by cancer cells for their uncontrolled proliferation and is observed during the development of autoimmune diseases [1, 2]. There are two pathways that lead to the activation of apoptosis. The extrinsic pathway is initiated through the activation of death receptors that belong to the TNF receptor superfamily, such as tumor necrosis factor (TNF)-related apoptosisinducing ligand (TRAIL) or Fas. The signal is transmitted via Fas-associated death domain protein (FADD)-dependent activation of caspase-8 and caspase-10, which in turn
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