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

Abstract

Tamer M Ibrahim,1,2 Christoph Ernst,1 Andreas Lange,1 Susanne Hennig,1 Frank M Boeckler1 1Laboratory for Molecular Design and Pharmaceutical Biophysics, Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Eberhard Karls University Tübingen, Tübingen, Germany; 2Pharmaceutical Chemistry Department, Faculty of Pharmacy, Kafrelsheikh University, Kafr El-Sheikh, EgyptCorrespondence: Tamer M IbrahimPharmaceutical Chemistry Department, Faculty of Pharmacy, Kafrelsheikh University, El-Geish Street, Kafr El-Sheikh 33516, EgyptEmail [email protected]: 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

Keywords

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