posted on 2015-09-30, 00:00authored byLogan
R. Hoggard, Yongqiang Zhang, Min Zhang, Vanja Panic, John A. Wisniewski, Haitao Ji
Selective
inhibition of α-helix-mediated protein–protein
interactions (PPIs) with small organic molecules provides great potential
for the discovery of chemical probes and therapeutic agents. Protein
Data Bank data mining using the HippDB database indicated that (1)
the side chains of hydrophobic projecting hot spots at positions i, i + 3, and i + 7 of
an α-helix had few orientations when interacting with the second
protein and (2) the hot spot pockets of PPI complexes had different
sizes, shapes, and chemical groups when interacting with the same
hydrophobic projecting hot spots of α-helix. On the basis of
these observations, a small organic molecule, 4′-fluoro-N-phenyl-[1,1′-biphenyl]-3-carboxamide, was designed
as a generic scaffold that itself directly mimics the binding mode
of the side chains of hydrophobic projecting hot spots at positions i, i + 3, and i + 7 of
an α-helix. Convenient decoration of this generic scaffold led
to the selective disruption of α-helix-mediated PPIs. A series
of small-molecule inhibitors selective for β-catenin/B-cell
lymphoma 9 (BCL9) over β-catenin/cadherin PPIs was designed
and synthesized. The binding mode of new inhibitors was characterized
by site-directed mutagenesis and structure–activity relationship
studies. This new class of inhibitors can selectively disrupt β-catenin/BCL9
over β-catenin/cadherin PPIs, suppress the transactivation of
canonical Wnt signaling, downregulate the expression of Wnt target
genes, and inhibit the growth of Wnt/β-catenin-dependent cancer
cells.