Fragment-based Differential Targeting of PPI Stabilizer Interfaces

Xavier Guillory, Madita Wolter, Seppe Leysen, Joao Filipe Neves, Ave Kuusk, Sylvia Genet, Bente Somsen, John Morrow, Emma Rivers, Lotte van Beek, Joe Patel, Robert Goodnow, Heike Schoenherr, Nathan Fuller, Qing Cao, Richard G Doveston, Luc Brunsveld, Michelle R Arkin, M Paola Castaldi, Helen BoydIsabelle Landrieu, Hongming Chen, Christian Ottmann

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Stabilization of protein-protein interactions (PPIs) holds great potential for therapeutic agents, as illustrated by the successful drugs rapamycin and lenalidomide. However, how such interface-binding molecules can be created in a rational, bottom-up manner is a largely unanswered question. We report here how a fragment-based approach can be used to identify chemical starting points for the development of small-molecule stabilizers that differentiate between two different PPI interfaces of the adapter protein 14-3-3. The fragments discriminately bind to the interface of 14-3-3 with the recognition motif of either the tumor suppressor protein p53 or the oncogenic transcription factor TAZ. This x-ray crystallography driven study shows that the rim of the interface of individual 14-3-3 complexes can be targeted in a differential manner with fragments that represent promising starting points for the development of specific 14-3-3 PPI stabilizers.

Original languageEnglish
Pages (from-to)6694–6707
Number of pages14
JournalJournal of Medicinal Chemistry
Volume63
Issue number13
DOIs
Publication statusPublished - 9 Jul 2020

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    Guillory, X., Wolter, M., Leysen, S., Neves, J. F., Kuusk, A., Genet, S., Somsen, B., Morrow, J., Rivers, E., van Beek, L., Patel, J., Goodnow, R., Schoenherr, H., Fuller, N., Cao, Q., Doveston, R. G., Brunsveld, L., Arkin, M. R., Castaldi, M. P., ... Ottmann, C. (2020). Fragment-based Differential Targeting of PPI Stabilizer Interfaces. Journal of Medicinal Chemistry, 63(13), 6694–6707 . https://doi.org/10.1021/acs.jmedchem.9b01942