Fragment-based Differential Targeting of PPI Stabilizer Interfaces

Guillory, X.; Wolter, M.; Leysen, S.; Neves, João Filipe; Kuusk, Ave; Genet, S.; Somsen, B.; Morrow, John Kenneth; Rivers, Emma; Beek, Lotte van; Patel, Joe; Goodnow, Robert A.; Schoenherr, Heike; Fuller, Nathan O.; Cao, Qing; Doveston, Richard G.; Brunsveld, Luc; Arkin, Michelle R.; Castaldi, P.; Boyd, Helen; Landrieu, Isabelle; Chen, Hongming; Ottmann, C.

doi:10.1021/acs.jmedchem.9b01942

Cited by 43 publications

(48 citation statements)

References 46 publications

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“…100 There is fragments that represent promising starting points for the development of specific 14-3-3 PPI stabilizers has also been reported resently. 101 Studies have shown that some small-molecule anticancer agents can prevent binding of 14-3-3 by inhibiting phosphorylation of the target protein. For example, UCN-01 can inhibit the activity of CHK1, TAK, CHK2 and other kinases, and thus phosphorylation of Ser216, the 14-3-3-binding site on CDC25C.…”

Section: Ther Apeuti C Targ E Ting Of 14 -3 -3 Protein Smentioning

confidence: 99%

The role of 14‐3‐3 proteins in cell signalling pathways and virus infection

Liu

Cao

Ding

et al. 2021

J Cellular Molecular Medi

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Section: Ther Apeuti C Targ E Ting Of 14 -3 -3 Protein Smentioning

confidence: 99%

The role of 14‐3‐3 proteins in cell signalling pathways and virus infection

Liu

Cao

Ding

et al. 2021

J Cellular Molecular Medi

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“…AZ-008: AZ-008 was discovered as a weak stabiliser of this PPI during a fragment-based drug discovery campaign 24 . FP and SPR experiments indicated that the compound has a reproducible two-fold stabilisation effect.…”

Section: Role In P53 Regulationmentioning

confidence: 99%

Regulation of p53 by the 14-3-3 protein interaction network: new opportunities for drug discovery in cancer

et al. 2020

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Most cancers evolve to disable the p53 pathway, a key tumour suppressor mechanism that prevents transformation and malignant cell growth. However, only ~50% exhibit inactivating mutations of p53, while in the rest its activity is suppressed by changes in the proteins that modulate the pathway. Therefore, restoring p53 activity in cells in which it is still wild type is a highly attractive therapeutic strategy that could be effective in many different cancer types. To this end, drugs can be used to stabilise p53 levels by modulating its regulatory pathways. However, despite the emergence of promising strategies, drug development has stalled in clinical trials. The need for alternative approaches has shifted the spotlight to the 14-3-3 family of proteins, which strongly influence p53 stability and transcriptional activity through direct and indirect interactions. Here, we present the first detailed review of how 14-3-3 proteins regulate p53, with special emphasis on the mechanisms involved in their binding to different members of the pathway. This information will be important to design new compounds that can reactivate p53 in cancer cells by influencing protein–protein interactions. The intricate relationship between the 14-3-3 isoforms and the p53 pathway suggests that many potential drug targets for p53 reactivation could be identified and exploited to design novel antineoplastic therapies with a wide range of applications.

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“…In recent studies, the reverse experiment, monitoring 15 N, 2 H-labeled 14-3-3ΔC protein in 1 H, 15 N-TROSY-HSQC experiments [ 103 ], was used to investigate the stabilizing effect of several compounds on the interaction of 14-3-3 with different unlabeled peptide epitopes derived from 14-3-3 cargo proteins [ 104 – 106 ]. E.g., a semi-synthetic ligand consisting of a fusicoccane diterpene core combined with different sugar moieties was designed to improve its properties as molecular glue for the 14-3-3/p53 complex [ 105 ].…”

Section: Reviewmentioning

confidence: 99%

NMR Spectroscopy of supramolecular chemistry on protein surfaces

Bayer¹,

Matena²,

Beuck³

2020

Beilstein J. Org. Chem.

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As one of the few analytical methods that offer atomic resolution, NMR spectroscopy is a valuable tool to study the interaction of proteins with their interaction partners, both biomolecules and synthetic ligands. In recent years, the focus in chemistry has kept expanding from targeting small binding pockets in proteins to recognizing patches on protein surfaces, mostly via supramolecular chemistry, with the goal to modulate protein–protein interactions. Here we present NMR methods that have been applied to characterize these molecular interactions and discuss the challenges of this endeavor.

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Fragment-based Differential Targeting of PPI Stabilizer Interfaces

Cited by 43 publications

References 46 publications

The role of 14‐3‐3 proteins in cell signalling pathways and virus infection

The role of 14‐3‐3 proteins in cell signalling pathways and virus infection

Regulation of p53 by the 14-3-3 protein interaction network: new opportunities for drug discovery in cancer

NMR Spectroscopy of supramolecular chemistry on protein surfaces

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