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

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(1H)-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(1H)-one and its 6-phenyl substituent into a tricyclic structure, linking position 5 of pyridin-2(1H)-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.

Keywords:

• pyridin-2(1H)-one derivatives
• one-pot synthesis
• molecular dynamics and design
• survivin-dimerization modulators

Acknowledgments

TMI is thankful to the GERLS (German–Egyptian Research Long-Term Scholarship) program of the German Academic Exchange Service (DAAD) for funding his PhD fellowship, and GERSS program (German–Egyptian Research Short-Term Scholarship/DAAD) for funding a research stay at Eberhard Karls University Tübingen. We thank Matthias R Bauer for generating the DEKOIS 2.0 benchmark set from survivin bioactives and Johannes Heidrich for preparing the raw 2D-RMSD matrix for plotting.

Author Contributions

TMI and FMB designed the experiments. TMI carried out all experiments. CE, AL, and SH helped in gene cloning and survivin expression and purification. TMI and FMB wrote the manuscript. FMB supervised the project and provided advice and expertise. All authors contributed to data analysis, drafting and revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Disclosure

FMB reports grants from the pharmaceutical industry outside the submitted work. The authors report no other conflicts of interest in this work.