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

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

30 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

Access to Document

10.1021/acs.jmedchem.9b01942Licence: CC BY-NC-ND

Cite this

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

@article{7500795032f24c0f9b64f669a8eb7ceb,

title = "Fragment-based Differential Targeting of PPI Stabilizer Interfaces",

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.",

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

year = "2020",

month = jul,

day = "9",

doi = "10.1021/acs.jmedchem.9b01942",

language = "English",

volume = "63",

pages = "6694–6707 ",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "13",

}

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

TY - JOUR

T1 - Fragment-based Differential Targeting of PPI Stabilizer Interfaces

AU - Guillory, Xavier

AU - Wolter, Madita

AU - Leysen, Seppe

AU - Neves, Joao Filipe

AU - Kuusk, Ave

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

Y1 - 2020/7/9

N2 - 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.

AB - 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.

U2 - 10.1021/acs.jmedchem.9b01942

DO - 10.1021/acs.jmedchem.9b01942

M3 - Article

C2 - 32501690

SN - 0022-2623

VL - 63

SP - 6694

EP - 6707

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 13

ER -

Fragment-based Differential Targeting of PPI Stabilizer Interfaces

Abstract

Access to Document

Fingerprint

Cite this