Small Molecules Simultaneously Inhibiting p53-Murine Double Minute 2 (MDM2) Interaction and Histone Deacetylases (HDACs): Discovery of Novel Multitargeting Antitumor Agents

p53-Murine double
minute 2 (MDM2) interaction and histone deacetylases (HDACs) are important
targets in antitumor drug development. Inspired by the synergistic
effects between MDM2 and HDACs, the first MDM2/HDACs dual inhibitors
were identified, which showed excellent activities against both targets.
In particular, compound 14d was proven to be a potent
and orally active MDM2/HDAC dual inhibitor, whose antitumor mechanisms
were validated in cancer cells. Compound 14d showed excellent
in vivo antitumor potency in the A549 xenograft model, providing a
promising lead compound for the development of novel antitumor agents.
Also, this proof-of-concept study offers a novel and efficient strategy
for multitargeting antitumor drug discovery.