Targeted covalent inhibitors of MDM2 using electrophile-bearing stapled peptides

Jiraborrirak Charoenpattarapreeda; Yaw Sing Tan; Jessica Iegre; Stephen J. Walsh; Elaine Fowler; Rohan S. Eapen; Yuteng Wu; Hannah F. Sore; Chandra S. Verma; Laura Itzhaki; David R. Spring

doi:10.1039/C9CC04022F

Targeted covalent inhibitors of MDM2 using electrophile-bearing stapled peptides†

Jiraborrirak Charoenpattarapreeda,

^a Yaw Sing Tan,^b Jessica Iegre,

^a Stephen J. Walsh,

^a Elaine Fowler,

^a Rohan S. Eapen,

^c Yuteng Wu,^a Hannah F. Sore,

^a Chandra S. Verma,

^bde Laura Itzhaki

^c and David R. Spring

*^a

Author affiliations

* Corresponding authors

^a Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK
E-mail: spring@ch.cam.ac.uk

^b Bioinformatics Institute, Agency for Science, Technology and Research (A*STAR), 30 Biopolis Street, #07-01 Matrix, Singapore

^c Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK

^d Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore

^e School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore

Abstract

Herein, we describe the development of a novel staple with an electrophilic warhead to enable the generation of stapled peptide covalent inhibitors of the p53–MDM2 protein–protein interaction (PPI). The peptide developed showed complete and selective covalent binding resulting in potent inhibition of p53–MDM2 PPI.

Chemical Communications

Targeted covalent inhibitors of MDM2 using electrophile-bearing stapled peptides†

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Targeted covalent inhibitors of MDM2 using electrophile-bearing stapled peptides

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