1,4,5-Trisubstituted Imidazole-Based p53–MDM2/MDMX Antagonists with Aliphatic Linkers for Conjugation with Biological Carriers

The tumor suppressor protein p53,
the “guardian of the genome”,
is inactivated in nearly all cancer types by mutations in the TP53 gene or by overexpression of its negative regulators,
oncoproteins MDM2/MDMX. Recovery of p53 function by disrupting the
p53–MDM2/MDMX interaction using small-molecule antagonists
could provide an efficient nongenotoxic anticancer therapy. Here we
present the syntheses, activities, and crystal structures of the p53–MDM2/MDMX
inhibitors based on the 1,4,5-trisubstituted imidazole scaffold which
are appended with aliphatic linkers that enable coupling to bioactive
carriers. The compounds have favorable properties at both biochemical
and cellular levels. The most effective compound 19 is
a tight binder of MDM2 and activates p53 in cancer cells that express
the wild-type p53, leading to cell cycle arrest and growth inhibition.
Crystal structures reveal that compound 19 induces MDM2
dimerization via the aliphatic linker. This unique dimerization-binding
mode opens new prospects for the optimization of the p53–MDM2/MDMX
inhibitors and conjugation with bioactive carriers.