Rational design and synthesis of 1,5-disubstituted tetrazoles as potent inhibitors of the MDM2-p53 interaction

Ewa Surmiak; Constantinos G Neochoritis; Bogdan Musielak; Aleksandra Twarda-Clapa; Katarzyna Kurpiewska; Grzegorz Dubin; Carlos Camacho; Tad A Holak; Alexander Dömling

doi:10.1016/j.ejmech.2016.11.029

Rational design and synthesis of 1,5-disubstituted tetrazoles as potent inhibitors of the MDM2-p53 interaction

Eur J Med Chem. 2017 Jan 27:126:384-407. doi: 10.1016/j.ejmech.2016.11.029. Epub 2016 Nov 16.

Authors

Ewa Surmiak¹, Constantinos G Neochoritis², Bogdan Musielak¹, Aleksandra Twarda-Clapa³, Katarzyna Kurpiewska¹, Grzegorz Dubin³, Carlos Camacho⁴, Tad A Holak⁵, Alexander Dömling⁶

Affiliations

¹ Department of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland.
² Department of Pharmacy, Drug Design Department, University of Groningen, 9713AV Groningen, The Netherlands.
³ Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Krakow, Poland; Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7a, 30-387 Krakow, Poland.
⁴ Department of Computational and Systems Biology, University of Pittsburgh, 3501 Fifth Avenue, Biomedical Science Tower 3, Pittsburgh, PA 15260, USA.
⁵ Department of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland; Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7a, 30-387 Krakow, Poland.
⁶ Department of Pharmacy, Drug Design Department, University of Groningen, 9713AV Groningen, The Netherlands. Electronic address: a.s.s.domling@rug.nl.

PMID: 27907876
DOI: 10.1016/j.ejmech.2016.11.029

Abstract

Using the computational pharmacophore-based ANCHOR.QUERY platform a new scaffold was discovered. Potent compounds evolved inhibiting the protein-protein interaction p53-MDM2. An extensive SAR study was performed based on our four-point pharmacophore model, yielding derivatives with affinity to MDM2 in the nanomolar range. Their binding affinity with MDM2 was evaluated using both fluorescence polarization (FP) assay and 2D-NMR-HSQC experiments.

MeSH terms

Chemistry Techniques, Synthetic
Drug Design*
Humans
Models, Molecular
Protein Binding / drug effects
Protein Domains
Proto-Oncogene Proteins c-mdm2 / chemistry
Proto-Oncogene Proteins c-mdm2 / metabolism*
Structure-Activity Relationship
Tetrazoles / chemical synthesis*
Tetrazoles / chemistry
Tetrazoles / pharmacology*
Tumor Suppressor Protein p53 / chemistry
Tumor Suppressor Protein p53 / metabolism*

Substances

Tetrazoles
Tumor Suppressor Protein p53
Proto-Oncogene Proteins c-mdm2