1 research outputs found
Discovery of Potent Mcl-1/Bcl-xL Dual Inhibitors by Using a Hybridization Strategy Based on Structural Analysis of Target Proteins
Mcl-1
and Bcl-xL are crucial regulators of apoptosis, therefore
dual inhibitors of both proteins could serve as promising new anticancer
drugs. To design Mcl-1/Bcl-xL dual inhibitors, we performed structure-guided
analyses of the corresponding selective Mcl-1 and Bcl-xL inhibitors.
A cocrystal structure of a pyrazolo[1,5-<i>a</i>]pyridine
derivative with Mcl-1 protein was successfully determined and revealed
the protein–ligand binding mode. The key structure for Bcl-xL
inhibition was further confirmed through the substructural analysis
of ABT-263, a representative Bcl-xL/Bcl-2/Bcl-w inhibitor developed
by Abbott Laboratories. On the basis of the structural data from this
analysis, we designed hybrid compounds by tethering the Mcl-1 and
Bcl-xL inhibitors together. The results of X-ray crystallographic
analysis of hybrid compound <b>10</b> in complexes with both
Mcl-1 and Bcl-xL demonstrated its binding mode with each protein.
Following further optimization, compound <b>11</b> showed potent
Mcl-1/Bcl-xL dual inhibitory activity (Mcl-1, IC<sub>50</sub> = 0.088
μM; and Bcl-xL, IC<sub>50</sub> = 0.0037 μM)