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      Small-Molecule Intervention At The Dimerization Interface Of Survivin By Novel Rigidized Scaffolds

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          Abstract

          Introduction

          Survivin is a nodal protein involved in several cellular pathways. It is a member of the IAP family and an integral component of the chromosomal passenger complex, where it binds to borealin and INCENP through its dimerization interface. By targeting survivin with a small molecule at its dimerization interface, inhibition of the proliferation of cancer cells has been suggested. With Abbott 8, a small-molecule dimerization inhibitor has been recently reported. The structure–activity relationship of this series of inhibitors implied that the middle pyridin-2(1 H)-one ring did not tolerate modifications of any kind.

          Methods

          Based on the synthetic strategy of Abbott 8 using multicomponent reactions, we synthesized a series of small molecules bearing a novel rigidized core scaffold. This rigidization strategy was accomplished by integrating the pyridin-2(1 H)-one and its 6-phenyl substituent into a tricyclic structure, linking position 5 of pyridin-2(1 H)-one to the phenyl substituent by rings of different sizes. The new scaffolds were designed based on in silico molecular dynamics of survivin.

          Results

          Binding of these rigidized scaffolds to the recombinant L54M mutant of survivin was evaluated, revealing affinities in the low micromolar range.

          Conclusion

          This easily accessible, new class of survivin-dimerization modulators is an interesting starting point for further lead optimization.

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          Most cited references 48

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          Control of apoptosis and mitotic spindle checkpoint by survivin.

          Progression of the cell cycle and control of apoptosis (programmed cell death) are thought to be intimately linked processes, acting to preserve homeostasis and developmental morphogenesis. Although proteins that regulate apoptosis have been implicated in restraining cell-cycle entry and controlling ploidy (chromosome number), the effector molecules at the interface between cell proliferation and cell survival have remained elusive. Here we show that a new inhibitor of apoptosis (IAP) protein, survivin, is expressed in the G2/M phase of the cell cycle in a cycle-regulated manner. At the beginning of mitosis, survivin associates with microtubules of the mitotic spindle in a specific and saturable reaction that is regulated by microtubule dynamics. Disruption of survivin-microtubule interactions results in loss of survivin's anti-apoptosis function and increased caspase-3 activity, a mechanism involved in cell death, during mitosis. These results indicate that survivin may counteract a default induction of apoptosis in G2/M phase. The overexpression of survivin in cancer may overcome this apoptotic checkpoint and favour aberrant progression of transformed cells through mitosis.
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            Ligand efficiency: a useful metric for lead selection.

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              AMBER, a package of computer programs for applying molecular mechanics, normal mode analysis, molecular dynamics and free energy calculations to simulate the structural and energetic properties of molecules

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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                DDDT
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                18 December 2019
                2019
                : 13
                : 4247-4263
                Affiliations
                [1 ]Laboratory for Molecular Design and Pharmaceutical Biophysics, Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Eberhard Karls University Tübingen , Tübingen, Germany
                [2 ]Pharmaceutical Chemistry Department, Faculty of Pharmacy, Kafrelsheikh University , Kafr El-Sheikh, Egypt
                Author notes
                Correspondence: Tamer M Ibrahim Pharmaceutical Chemistry Department, Faculty of Pharmacy, Kafrelsheikh University , El-Geish Street, Kafr El-Sheikh33516, Egypt Email tamer.ibrahim2@gmail.com
                Article
                224561
                10.2147/DDDT.S224561
                6927794
                © 2019 Ibrahim et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 5, Tables: 2, References: 60, Pages: 17
                Categories
                Original Research

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