1 research outputs found
De-Novo Designed Library of Benzoylureas as Inhibitors of BCL‑X<sub>L</sub>: Synthesis, Structural and Biochemical Characterization
The
prosurvival BCL-2 proteins are attractive yet challenging targets
for medicinal chemists. Their involvement in the initiation and progression
of many, if not all, tumors makes them prime targets for developing
new anticancer therapies. We present our approach based on de novo
structure-based drug design. Using known structural information from
complexes engaging opposing members of the BCL-2 family of proteins,
we designed peptidomimetic compounds using a benzoylurea scaffold
to reproduce key interactions between these proteins. A library stemming
from the initial de novo designed scaffold led to the discovery of
ligands with low micromolar potency (<i>K</i><sub>D</sub> = 4 ÎĽM) and selectivity for BCL-X<sub>L</sub>. These compounds
bind in the canonical BH3 binding groove in a binding mode distinct
from previously known BCL-2 inhibitors. The results of our study provide
insight into the design of a new class of antagonists targeting a
challenging class of protein–protein interactions