Open AccessFragment-based Differential Targeting of PPI Stabilizer Interfaces
Author(s) -
X. Guillory,
M. Wolter,
S. Leysen,
João Filipe Neves,
Ave Kuusk,
S. Genet,
B. Somsen,
John Kenneth Morrow,
Emma L. Rivers,
Lotte van Beek,
Joe Patel,
Robert A. Goodnow,
Heike Schoenherr,
Nathan O. Fuller,
Qing Cao,
Richard G. Doveston,
Luc Brunsveld,
Michelle R. Arkin,
P. Castaldi,
Helen Boyd,
Isabelle Landrieu,
Hongming Chen,
C. Ottmann
Publication year - 2020
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.9b01942
Subject(s) - chemistry , adapter (computing) , small molecule , signal transducing adaptor protein , suppressor , stabilizer (aeronautics) , computational biology , rational design , transcription factor , combinatorial chemistry , stereochemistry , biochemistry , signal transduction , genetics , gene , biology , computer science , mechanical engineering , engineering , operating system
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.