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 Boyd; Isabelle Landrieu; Hongming Chen; Christian Ottmann

doi:10.1021/acs.jmedchem.9b01942

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 Boyd

Isabelle Landrieu (Corresponding author), Hongming Chen (Corresponding author), Christian Ottmann (Corresponding author)

Research output: Contribution to journal › Article › Academic › peer-review

45 Citations (Scopus)

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 language	English
Pages (from-to)	6694–6707
Number of pages	14
Journal	Journal of Medicinal Chemistry
Volume	63
Issue number	13
DOIs	https://doi.org/10.1021/acs.jmedchem.9b01942
Publication status	Published - 9 Jul 2020

Funding

We acknowledge François-Xavier Cantrelle for assistance on NMR data acquisition. The NMR facilities were funded by the Nord Region Council, CNRS, Institut Pasteur de Lille, the European Community (ERDF), the French Ministry of Research, and the University of Lille and by the CTRL CPER, cofunded by the European Union with the European Regional Development Fund (ERDF), by the Hauts de France Regional Council (contract no. 17003781), Métropole Européenne de Lille (contract no. 2016_ESR_05), and French State (contract no. 2017-R3-CTRL phase 1).We acknowledge support for the NMR facilities from TGE RMN THC (CNRS, FR-3050) and FRABio (Univ. Lille, CNRS, FR-3688). The research is supported by funding from the European Union through the AEGIS (H2020-MSCA-ITN-2015, grant no. 67555), and the TASPPI project (H2020-MSCA-ITN-2015, grant no. 675179). J.F.N and I.L acknowledge LabEx (Laboratory of Excellence) for financial support on the scope of the DISTALZ consortium (ANR, ANR-11-LABX-009).

Funders	Funder number
European Union's Horizon 2020 - Research and Innovation Framework Programme	675179
Université de Lille
European Commission
Centre National de la Recherche Scientifique
European Regional Development Fund

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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

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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.",

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Guillory, X, Wolter, M, Leysen, S, Neves, JF, Kuusk, A, Genet, S, Somsen, B, Morrow, J, Rivers, E, van Beek, L, Patel, J, Goodnow, R, Schoenherr, H, Fuller, N, Cao, Q, Doveston, RG, Brunsveld, L, Arkin, MR, Castaldi, MP, Boyd, H, Landrieu, I, Chen, H & Ottmann, C 2020, 'Fragment-based Differential Targeting of PPI Stabilizer Interfaces', Journal of Medicinal Chemistry, vol. 63, no. 13, pp. 6694–6707 . https://doi.org/10.1021/acs.jmedchem.9b01942

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AU - Guillory, Xavier

AU - Wolter, Madita

AU - Leysen, Seppe

AU - Neves, Joao Filipe

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AU - Genet, Sylvia

AU - Somsen, Bente

AU - Morrow, John

AU - Rivers, Emma

AU - van Beek, Lotte

AU - Patel, Joe

AU - Goodnow, Robert

AU - Schoenherr, Heike

AU - Fuller, Nathan

AU - Cao, Qing

AU - Doveston, Richard G.

AU - Brunsveld, Luc

AU - Arkin, Michelle R.

AU - Castaldi, M Paola

AU - Boyd, Helen

AU - Landrieu, Isabelle

AU - Chen, Hongming

AU - Ottmann, Christian

PY - 2020/7/9

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JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 13

ER -

Fragment-based Differential Targeting of PPI Stabilizer Interfaces

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