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2013 ; 4
(2
): 306-11
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High-Throughput Selectivity Assays for Small-Molecule Inhibitors of
?-Catenin/T-Cell Factor Protein-Protein Interactions
#MMPMID24900664
Zhang M
; Catrow JL
; Ji H
ACS Med Chem Lett
2013[Feb]; 4
(2
): 306-11
PMID24900664
show ga
Two homogeneous high-throughput assays, AlphaScreen and fluorescence
polarization, were established to quantify inhibitor selectivity between
different protein-protein complexes. As a first case study, they have been
successfully applied to the key protein-protein interactions in the downstream
sites of the canonical Wnt signaling pathway. The aberrant formation of the
?-catenin/T-cell factor (Tcf) complex is the major driving force for many cancers
and fibroses. Crystallographic and biochemical studies reveal that the binding
modes of Tcf, E-cadherin, and adenomatous polyposis coli (APC) to ?-catenin are
identical and mutually exclusive. In the present study, two highly sensitive and
robust assays were established to quantitatively evaluate inhibitor selectivity
between ?-catenin/Tcf, ?-catenin/E-cadherin, and ?-catenin/APC interactions. A
pilot screen demonstrated the feasibility of the assays and yielded four hits for
the disruption of ?-catenin/Tcf interactions. A potent and dual-selective
?-catenin/Tcf inhibitor was identified.