Dataset Information

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.

SUBMITTER: Ibrahim TM

PROVIDER: S-EPMC6927794 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Ibrahim Tamer M TM Ernst Christoph C Lange Andreas A Hennig Susanne S Boeckler Frank M FM

Drug design, development and therapy 20191218

<h4>Introduction</h4>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-a ...[more]

PMID: 31908412

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Dataset Information

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

Introduction

Methods

Results

Conclusion

Publications

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

Similar Datasets

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